text: After being rather busy on what I guess was sunday and then having a power outage that lasted most of the night, I kinda got WAY behind on email. -devel alone was up to over 1000 messages, 500 more than it should have been had I been keeping up. I was kinda busy again today, finished most everything by tonight, but I've just spent the past 4-5 hours pretty much trying to catch up. I may have missed things and certainly know that since mutt has been in -devel since about 11:30 today (it's currently 05:38 the next day and I haven't slept yet) that I missed things like gecko's message about replying to DPL stuff. (oops, again) The good news is that I'm pretty much about done with -devel which is where most of the mail I haven't read is. If you've sent me something in the past 36 hours and expected an answer by now and haven't got one, I'll get to it, promise. I need a UPS. =p -- "Shall we play a game?" -- WOPR


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Colonial Population. Divergence between the cultures of the colonies, tried to distance themselves from Native Americans, population grew rapidly through immigration and natural increase- by late 17th century Europeans and Africans became dominant. America in 1700. Colonial Population.
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subset: commoncrawl


text:
Synthese, vol. 166, issue 1 (2009) pp. 187-213
Abstract The thesis of methodological individualism in social science is commonly divided into two different claims - explanatory individualism and ontological individ- ualism. Ontological individualism is the thesis that facts about individuals exhaustively determine social facts. Initially taken to be a claim about the identity of groups with sets of individuals or their properties, ontological individualism has more recently been understood as a global supervenience claim. While explanatory individualism has remained controversial, ontological individualism thus understood is almost uni- versally accepted. In this paper I argue that ontological individualism is false. Only if the thesis is weakened to the point that it is equivalent to physicalism can it be true, but then it fails to be a thesis about the determination of social facts by facts about individual persons. Even when individualistic facts are expanded to include people's local environments and practices, I shall argue, those still underdetermine the social facts that obtain. If true, this has implications for explanation as well as ontol- ogy. I first consider arguments against the local supervenience of social facts on facts about individuals, correcting some flaws in existing arguments and affirming that local supervenience fails for a broad set of social properties. I subsequently apply a similar approach to defeat a particularly weak form of global supervenience, and consider potential responses. Finally, I explore why it is that people have taken ontological individualism to be true.
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Bad Habits Persist in Designs for Future Malls
"Ah, if only the designers and developers of shopping malls paid as much attention to the foot traffic outside the mall as they do to the orchestrated promenade within it."
"At the 2009 International Council on Shopping Centers convention held in Las Vegas last month, pedestrian-oriented development was not top of mind (though in a 3.2 million-square-foot convention center, walking was a defining part of the experience). Despite a nearly 50 percent drop in attendance from prior years, most talk at ICSC was of how business as usual could resume once 'things came back.'"
"I was brought to ICSC as a juror for the organization's inaugural Future Image Architecture Competition, which asked entrants to imagine the shopping mall of the future. My expectations for the entries were high - and probably too preconceived. This seems like a watershed moment for malls, much as it does for housing. Surely, I thought, the entries will reflect the extent to which business as usual - i.e., massive anchor retail tenants surrounded by thousands (even millions) of square feet of specialized yet mass retail, in settings only accessible by car - cannot possibly continue. Having just witnessed the Sony-backed Metreon mall in San Francisco shift from its failed existence as a "state of the art technology and entertainment marketplace" to a modest farmer's market, I'd seen the writing on the wall. Hadn't the shopping center folks?"
"Some have, but surprisingly, many haven't."


text: A General Motors hydrogen fuel cell car is on display on Capitol Hill in Washington on December 5, 2008. Meanwhile, GM's Richard Wagoner, Chrysler's Robert Nardelli, Ford's Alan Mulally and UAW's Ron Gettelfinger were testifying before the House Financial Services committee about the state of the US automobile manufacturing industry. Chrysler, GM and Ford are asking Congress for billions of dollars to help the industry weather the current economic crises. (UPI Photo/Roger L. Wollenberg)


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Results 1 to 4 of 4
03-20-09, 13:04 #1Registered User
- Join Date
- Mar 2009
- Posts
- 2
Unanswered: Possible?: Pair Off Matching Rows But Don't Pair It Off Again With Other Matches
Hi All,
I'm using VB6 and Acccess.
I want to pair off two records/rows. Once these records/rows are paired off I don't want a third, fourth, fifth, etc... record to pair off with records already paired off (see example below).
I've been struggling with this for quite some time and I was wondering if anyone could help me:
If I had a table [First Name], [Last Name], [City], [Pair Off]
Scenario (Raw Data):
Row1: Bob, Marley, New York
Row2: Bob, Marley, New York
Row3: Bob, Marley, California
Which I want to turn it into (Final Data):
Row1: Bob, Marley, California, Pairset 1
Row2: Bob, Marley, New York, Pairset 1
Row3: Bob, Marley, New York,
How would I do this?
Programmically in VB6 I could do this but I'd rather do it through queries.
The reason why I don't want to do it programmically is a few reasons:
1. It'll be faster if I didn't
2. It'll be cleaner
3. I keep getting a locked error (BUG: "Could Not Update; Currently Locked" Error Message Raised by Second Edit Attempt in a Transaction) and I can't figure out how to install MSDASQL.
4. Keeping the table open for a long time is not ideal (as I've read somewhere...)
What I did programmically was
open the table for all records "New York" (V1)
open the same table for records "California" (V2)
Update [Pair Off] where [First Name] and [Last Name] are the same in both views (V1 and V2). If Recordcount is odd, don't update the last record.
This process takes a really long time to process because of the connection from VB6 to Access and as mentioned before, the record is locked because of the multiple views.
One thing which I have tried is to create two queries "New York" and "California". I then created a new table
SELECT NY.FIRST, NY.LAST, NY.CITY, NY.PairOff
GROUP BY NY.FIRST, NY.LAST, NY.CITY, NY.PairOff;
I don't think this is exactly what I want in the pair off and it won't (of course) give me the rest of the data i.e. ROW 3 above.
Any help would be great, many thanks.
03-25-09, 18:32 #2Moderator
Provided Answers: 15
- Join Date
- Mar 2009
- Posts
- 5,442
One solution I can think of (they certainly are others) is:
1) Create a public function like this:
Public Function PairOff(Anything As Variant) As String Static lngCount As Long If Anything = "{Initialize}" Then lngCount = -1 lngCount = lngCount + 1 PairOff = "Pair Off " & CStr(lngCount) End Function
INSERT INTO TableDestination ( [First Name], [Last Name], City, [Pair Off] ) SELECT [First Name], [Last Name], City, PO FROM (SELECT [First Name], [Last Name], City, PairOff([City]) AS PO FROM (SELECT DISTINCT [First Name], [Last Name], City FROM TableSource))
PairOff("{Initialize}") CurrentDb.Execute <Query>
04-01-09, 21:19 #3Registered User
- Join Date
- Mar 2009
- Posts
- 2
Thanks for your reply. Unfortunately, I'm not getting the result I'm looking for - at least based on the way I re-did on my computer.
The results I got was
California Pairoff 1
New York Pairoff 2
I was hoping to get something like this
New York Pairoff 1
New York Pairoff 1
and if I had more "New Yorks" it would be
New York Pairoff 2
New York Pairoff 2.
To be quite honest, I'm still trying to understand your approach as it is quite fancy and I'm not that advanced enough to follow - but I am definitely interested in what's going on and will be looking into what's happening.
Thanks again!
04-02-09, 10:44 #4Moderator
Provided Answers: 15
- Join Date
- Mar 2009
- Posts
- 5,442
It would be easier if you could supply the general rule that determines how the "pairoff x" are attributed. It's not evident to extrapolate from one or two examples.
Have a nice day!


text:
284: Supercalifragalacticinterplanetentiary
Rachel's here and we start right off getting racist. We try to distract ourselves with the first beer of the week but Vivi can't help but continue and she follows this up by applying for a job at Buzzfeed via podcast. Again we blast one beer and praise another. We also discuss how aging beer in used barrels is better than used condoms. We don't want to know what might grow out of THAT concoction.
Moving forward, Rachel talks about the highs and lows of her holiday here after graduating from WVU. This includes wine tasting, brewery tours, new restaurants, and a day getting lost around downtown San Diego. Victoria and Rachel saw the new X-Men movie and they discuss their thoughts on it. This sends Victoria into a Comic Nerd lesson.
Victoria and Rachel also enjoyed a great concert featuring a couple new favorite bands: Nickle Creek and Secret Sisters. This gets us into a discussion about concerts past and certain preferences we've developed. We try the third beer of the evening and Victoria's brain leads us off on an awesome side track of strange words.
Allison and Dave got married and we share our love for them AND that awesome wedding. We were sad to have to leave early but Vivi had an appointment with an iguana, or Iggy as we call her. Meanwhile Rachel and I went to Slaters and Stone to start a week of WINE AND BEER!
We hit up Rough Draft Brewing, Hess Brewing, and Intergalactic Brewing all in one day. Then we visited Orfila Vineyards for a tasting the same weekend. We talk about the recent fires throughout San Diego and how strange it is that they struck so early in the year. This and a quick end to the show.


text:
Revolutionary War. 13 Original Colonies vs. Great Britain 1775-1783. Articles of Confederation. 1781-1789s. Timeline of Major Events. 1775 - Battle of Lexington and Concord Second Continental Congress convenes 1776 - Jefferson writes Declaration of Independence
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Articles of Confederation
Second Continental Congress (1775) meets
-Appoints GW as commander of Continental Army -John Hancock is president of 2nd C.C.
Ticonderoga (May, 1775)-Need ammo! Head to fort in northern NY for supplies
-Ethan Allen and the Green Mountain Boys & Benedict Arnold capture over 50 cannons and take to Boston
Battle of Bunker Hill (summer, 1775) - "Don't shoot until you see the whites of their eyes"
-British "took the hill" but lost 2x as many men
-50 page pamphlet; very convincing!
-Author Thomas Paine -British immigrant
-Jan, 1776, becomes a best seller
-Called King George III "enemy to liberty"
When war erupted in 1775, it seemed clear that Britain would win. It had a large, well-organized land army, and the Royal Navy was unmatched on the sea. Many of the British troops in the Revolutionary War were veterans who had fought in the French and Indian War. On the other hand, the Americans had only a collection of undisciplined militiamen who had never fought before. The Americannavy was small and no match for the thousand ships in the royal fleet. The state of the army did improve after George Washington whipped the Continental Army into a professional fighting force, but the odds still seemed heavily stacked in Britain's favor.
Nonetheless, the Americans believed that they did have a strong chance of success. They had a lot at stake: unlike the British, they were fighting on their home turf to protect their own homes and families. Perhaps most important, they were also fighting a popular war—a majority of the colonists were patriots who strongly supported the fight for independence. Finally, though most Americans had no previous military experience, their militia units were usually close-knit bands of men, often neighbors, who served together in defense of their own homes. They elected their own officers —usually men who did have some military training but who also knew the territory well. This native officer corps was a great source of strength, and as a result, American morale was generally higher than morale in the Royal Army.
Geography also gave the Americans an advantage that proved to be a major factor in the war's outcome. To the British forces, the North American terrain was unusually rugged: New England was rocky and cold in winter, the South was boggy and humid in the summer, and the western frontier was almost impenetrable because of muddy roads and thick forests. In addition, because American settlements were spread out across a vast range of territory, the British had difficulty mounting a concentrated fight and transporting men and supplies. American troops, on the other hand, were used to the terrain and had little trouble. Finally, the distance between England and the United States put a great strain on Britain, which spent a great deal of time, energy, and money ferrying soldiers and munitions back and forth across the Atlantic.
Though the war went on for several years, American popular supportremained high, especially after France and Spain entered the fray,. The motivation for rebellion remained strong at all levels of society, not merely among American military and political leaders. Many historians believe that it was this lasting popular support that ultimately enabled the United States to fight as long as it did. Although the United States did not really "win" the war—there were no clearly decisive battles either way—it was able to survive long enough against the British to come to an impasse. French and Spanish assistance certainly helped the Americans, but without the grassroots support of average Americans, the rebellion would have quickly collapsed.
Meanwhile, support in England for the war was low. In Parliament, many Whigs (a group of British politicians representing the interests of religious dissenters, industrialists, and others who sought reform) denounced the war as unjust. Eight years of their carping, combined with the Royal Army's inability to win a decisive victory, fatigued the British cause and helped bring the Revolutionary War to an end.
After numerous battles, the turning point in the war came in 1777 at the Battle of Saratoga in upstate New York. When American forces won, their victory encouraged France to pledge its support for the United States in the Franco-American Alliance of 1778. A year later, Spain followed suit and also entered the war against Britain. Spain, hoping to see Britain driven out of North America, had tacitly supported the Americans by providing them with munitions and supplies since the beginning of the war. Their entry as combatants took pressure off the Americans, as Britain was forced to divert troops to fight the Spanish elsewhere. Finally, the Netherlands entered the war against Britain in 1780.
1781- General Cornwallissurrendersto General George Washington at the Battle or Yorktown-Fortified by the Franco-American Alliance, the Americans maintained an impasse
-Scattered battles persisted until 1783, but the British, weary of the stalemate, decided to negotiate peace
-War came to an official close in September 1783-Britain, the United States, France, and Spain negotiated the Peace of Paris. -Treaty granted western lands to the Americans and recognized the United States as a new and independent country. -The last British forces departed, leaving the American government in full control of the new nation.-U.S. boundary – west to Mississippi River-France took back Canada- Spain controls Florida
The Articles of the Confederation


text:
sharing with Sunday Sketches
Feb 16, 2013
Cuddling in Pink Hair
sharing with Sunday Sketches
26 comments:
Quel regard !!! Elle est une grande séductrice!ReplyDelete
Gros bisous
Love the pink hair! And her lips are UH-MAZE-ING!ReplyDelete
thank you so much!ReplyDelete
what a lovely idea, the pink hair is so cool :)
Hi Tammie,ReplyDelete
Beautiful, and love the pink hair, just perfect for cuddling up in.. :)
She is so beautiful and love the tiny girl on her hair ~ very creative sketching! ^_^ReplyDelete
I love the pink hair! I used to have pink hair and this picture makes me miss it!ReplyDelete
What fun! Do you think it smells of strawberries?ReplyDelete
I used to have a purple streak in my hair when I was at art college and it used to fade to pink when i swam a lot... and I loved it... so I totally get why her pink hair makes her happy...xxReplyDelete
I have a thing about ladies with pink hair, maybe you know that! Pretty!ReplyDelete
Look at her adorable face! She is gorgeous!ReplyDelete
You have such an amzing imagination Tammie:) I love your girlsReplyDelete
How fun! I have always wondered why sometimes I can feel something in my hair. I never thought of a miniature person may be lounging in it! The lady with the pink hair has a beautiful face. Her full lips are divine!ReplyDelete
I checked out you other blog of photography and poetry, amazing, simply amazing...the light is stunning of every picture. How do you do it? It is so dreary here in winter in Canada not to far from Montana!ReplyDelete
Well, I'd cuddle up in her hair too. I'm loving all these new faces, Tammie! And super love this gal's clear blue eyes. Catlike and wonderful!ReplyDelete


text:
You're a young lawyer, setting out to start your own practice, so of course the first and most important thing you have to do is pick a name for your firm.
Firm naming is all the rage these days, with many firms going with just a single name, like Skadden, or Cravath. Other firms have chosen to go the more creative, slightly-edgy route, with Morrison Foerster going by MoFo, and Strook and Strook taking on the Jersey Shore inspired Stroo-Stroo.
If you want to be ahead of the naming curve though, and if you want to make the big bucks you'd better be, you'll want to go with the newest craze, dropping spaces and conjunctions.
BOOM! That's a law firm name. Just watch at the money pours in.*
*cf. The name-pronunciation effect: Why people like Mr. Smith more than Mr. Colquhoun, by Laham, Koval, and Alter, published in the Journal of Experimental Psychology. Across several different studies, Laham, Koval, and Alter found that easy to pronounce names were far more likely to be liked than hard to pronounce and unusual names.
Of particular note, the researchers looked at complexity of names in law firm hierarchies, picking 500 names at random from NLJ 250 law firm websites. Even after controlling for the effects of racial bias in hiring and promotion (by comparing Anglo-American names against other Anglo-American names, and foreign names against other foreign names) they found a correlation between simpler names and promotion into partnership.
It stands to reason that these results would be applicable to a small, start-up law firm, which must attract clients faced with a number of choices in legal counsel, and establish relationships with other firms in order to receive referral work. As such, a difficult to read or confusing name, such as RamsonBigsby, could significantly hurt a law firm, while a less creative and more familiar looking name would be beneficial.


text:
Contact Info / Websites
Recent Movie Reviews
HOTPANTS! - Animated Me
Rated 5 / 5 stars
Wow that's an awkard scene XD, great animation.
Crunchlins responds:
Thanks very much!
There She Is!! final step
Rated 5 / 5 stars
best ending ever. great story with an even greater message
Pokemon is TOO HARD!!!
Rated 5 / 5 stars
Freaking awesome like always, keep it u
Crunchlins responds:
Thanks for the support mate!
Recent Art Reviews
Rated 5 / 5 stars
Amazing, great job man, it looks spot on
Fight Sequence Test
Rated 5 / 5 stars
Looks really good


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Daily briefs of the top Christian news and persecution stories impacting believers around the world.
In today's edition:
- Islamists in Pakistan Kill Two Christians at Courthouse
- Eight Killed in Nigerian Christian Village
- Adoption Increases Up 26 Percent for 2010, Bethany Says
- Pastor Killed by Gunman in Dagestan
Islamists in Pakistan Kill Two Christians at Courthouse
International Christian Concern has learned that Islamists killed two Christians accused of blasphemy as they left court in Faisalabad, Pakistan Monday afternoon. Police were transporting the Christians from the court to jail when masked Islamists shot them to death. A policeman accompanying the Christians was also seriously wounded by the attackers, who escaped. Pastor Rashid Emmanuel and his brother Sajid Emmanuel were arrested on July 2 after Muslims accused them of writing a pamphlet with blasphemous remarks about the Prophet Muhammad. The charges were based on hand-written and photo-copied pamphlets with remarks Jonathan Racho, ICC's Regional Manager for South Asia, said, "It's outrageous that the Islamists managed to kill the Christians while they were under police custody. This is another indication of the value and the status of Christians within Pakistan."
Eight Killed in Nigerian Christian Village
The Christian Post reports that eight people are dead after attackers targeted a Christian village near Jos, Nigeria on July 18. Seven houses and a church burned to the ground in Maza, and the wife, two children and grandson of a pastor were killed in the violence. Military spokesman Lieutenant Colonel Kingsley Umo told Agence France-Presse that the attackers shot sporadically in the air to lure sleeping residents outside their homes before they were killed. The attackers are believed to be Muslim Fulani herdsmen. Violent disputes between Nigeria's traditionally Christian south and traditionally Muslim north have flared since the start of this year. Local rights groups say that 1,500 people have been killed in the violence.
Adoption Increases Up 26 Percent for 2010, Bethany Says
Christian Newswire reports that attention to January's earthquake in Haiti seems to have triggered a rise in U.S. adoptions. Bethany Christian Services, the nation's largest adoption agency, says overall international and domestic adoption placements have risen 26 percent over the same time period in 2009. The organization says intercountry adoption placements up 66 percent and intercountry adoption inquiries ahead by more than 5,000 requests during the same six month time period of 2009, totaling an unprecedented 10,567 inquiries. Bethany ascribes these increases in part to the Haiti crisis and the need to find safe homes for children who lost one or both parents during the earthquake. "The figures Bethany released show strong improvement as we confront the global orphan crisis, but the need still remains as there are still an incredible number of orphaned children who wait for their 'forever family'," said Bill Blacquiere, president and CEO at Bethany Christian Services.
Pastor Killed by Gunman in Dagestan
ASSIST News Service reports that a pastor in the Dagestan region of Russia was killed as he left church on July 15. Artur Suleimanov, 49, died at a hospital an hour after opened fire on him in front of Hosanna House of Prayer in Makhachkala. "No one else was injured the attack, but witnesses of Suleimanov's murder suppose that the gunman's agenda for murdering a Christian pastor, such as Suleimanov, would most likely have to do with Islam supremacy," said a spokesperson for Barnabus Fund, which worked with the pastor. "Suleimanov was a convert himself from Islam, and he boldly led his congregation to Christ under protestant dogma, free from Islam's rule."


text:
Light solutions free vector
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N-methyl-D-aspartic acid (NMDA) receptors are critical for both normal brain functions and the pathogenesis of schizophrenia. We investigated the functional changes of glutamatergic receptors in the pyramidal cells and fast-spiking (FS) interneurons in the adolescent rat prefrontal cortex in MK-801 model of schizophrenia. We found that although both pyramidal cells and FS interneurons were affected by in vivo subchronic blockade of NMDA receptors, MK-801 induced distinct changes in αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors in the FS interneurons compared with pyramidal cells. Specifically, the amplitude, but not the frequency, of AMPA-mediated miniature excitatory postsynaptic currents (mEPSCs) in FS interneurons was significantly decreased whereas both the frequency and amplitude in pyramidal neurons were increased. In addition, MK-801-induced new presynaptic NMDA receptors were detected in the glutamatergic terminals targeting pyramidal neurons but not FS interneurons. MK-801 also induced distinct alterations in FS interneurons but not in pyramidal neurons, including significantly decreased rectification index and increased calcium permeability. These data suggest a distinct cell-type specific and homeostatic synaptic scaling and redistribution of AMPA and NMDA receptors in response to the subchronic blockade of NMDA receptors and thus provide a direct mechanistic explanation for the NMDA hypofunction hypothesis that have long been proposed for the schizophrenia pathophysiology.
Glutamatergic hypotheses of schizophrenia are based on the ability of N-methyl-D-aspartic acid (NMDA) receptor antagonists such as phencyclidine, ketamine, or MK-801 to induce psychotic symptoms closely resembling those of schizophrenia (Farber, 2003; Javitt, 2004; Javitt and Zukin, 1991; Jentsch and Roth, 1999; Krystal et al., 1994; Lahti et al., 1995; Marino and Conn, 2002; Moghaddam, 2003; Olney and Farber, 1995; Pinault, 2008). Although the exact mechanisms remain elusive, it is generally believed that NMDA antagonists reduce the stimulation of NMDA receptors in γ-aminobutyric acid-ergic (GABAergic) interneurons, leading to disinhibition of glutamatergic pyramidal neurons, which in turn induces hyper-excitability in pyramidal neurons and thus excessive glutamate release in the limbic systems (Benes, 2000; Jentsch and Roth, 1999; Lisman et al., 2008; Moghaddam et al., 1997; Olney et al., 1991). The critical players in this hypothesis are the GABAergic interneurons, which play an essential role in the regulation of activities of pyramidal cells in the cortical circuits (Lisman et al., 2008; Nakazawa et al., 2011). Indeed, clear deficits of GABAergic transmissions were reported in the brains of patients with schizophrenia (Lewis et al., 2005). Deficient GABA function is known to be closely associated abnormal oscillations and synchrony that are critical for the generation of cognitive deficits and other symptoms of the disorder (Uhlhaas and Singer, 2006, 2010). In animal models, repeated application of NMDA receptor antagonists evokes behavioral and neurochemical changes (Carpenter and Koenig, 2008; Gunduz-Bruce, 2009; Lindsley et al., 2006; Rujescu et al., 2006). For example, subchronic administration of NMDA receptor antagonists decreases the expression of parvalbumin (PV) in GABAergic interneurons (Abekawa et al., 2007; Braun et al., 2007; Cochran et al., 2003; Coleman et al., 2009), disrupts cortical inhibition (Grunze et al., 1996; Li et al., 2002; Zhang et al., 2008), induces working memory deficits (Coleman et al., 2009), attentional deficits and increased impulsivity (Amitai and Markou, 2009; Amitai et al., 2007).
Our recent studies showed that excitatory inputs onto immature fast-spiking (FS) interneurons have strong NMDA receptor-mediated currents that progressively weaken with age, becoming small or absent in adult FS interneurons in the rat prefrontal cortex (PFC) (Wang and Gao, 2009, 2010). These properties suggest that FS interneurons may be particularly vulnerable to environmental or drug stimulation (e.g., MK-801) during cortical development (Xi et al., 2009b). Indeed, in a strain of genetically modified mice in which the NMDAR subunit NR1 was conditionally knocked out in GABA neurons, including PV-positive cells, failed to produce significant effects when the knockout occurred after adolescence. However, when the deletion was conducted early in development, adult mice developed schizophrenia-like behavioral alterations (Belforte et al., 2010). Despite this large body of evidence, it remains unclear how NMDA receptor antagonist affects the synaptic functions of prefrontal neurons, particularly in FS interneurons. It is also unknown why GABAergic interneurons are more vulnerable to NMDA receptor antagonist among different cell-types (Wang et al., 2008a) and how the proposed hypofunction of glutamatergic systems occur in the pathogenesis of schizophrenia, particularly during the adolescent period. We therefore explored how subchronic treatment with MK-801 resulted in the disruption of glutamatergic transmission in adolescent rat prefrontal neurons by comparing the changes of NMDA and AMPA receptors in FS interneurons with those in pyramidal neurons. We found that MK-801 induced distinct cell-type specific alterations of glutamatergic receptors in the pyramidal neurons and FS interneurons.
We used 98 female Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) at adolescent ages PD30 to PD39 (Spear, 2000; Tseng and O'Donnell, 2007; Wang and Gao, 2010). The rats were maintained on a 12-hour light/dark cycle and were fed ad libitum. To be consistent, we continued to use female rats in which we have reported significant changes of NMDA receptors in the MK-801 model (Xi et al., 2009a; Xi et al., 2011; Xi et al., 2009b). In fact, although we did not observe a significant gender difference, some studies suggested that PCP-, MK-801-, and ketamine-induced effects are more reproducible in female animals (Dickerson and Sharp, 2006; Farber et al., 1995; Nakki et al., 1996). The animals were treated under National Institutes of Health animal use guidelines, and the experimental protocol was approved by the Institutional Animal Care and Use Committee at Drexel University College of Medicine. Because we could use only one rat each day for electrophysiological recording, the rats were treated with either MK-801 (0.1 mg/kg, intraperitoneally [i.p.], daily) or 0.9% saline as vehicle control for 5 consecutive days from PD30 to PD39. This dosage is based on our recent reports in which 0.1 mg/kg MK-801 were found to be effective in inducing changes of NMDA receptors in both transcription and protein levels (Xi et al., 2011; Xi et al., 2009b).
The detailed procedure is described in our previous publications (Gao et al., 2001; Wang and Gao, 2009, 2010). The rats (at ages of PD36–45) were deeply anesthetized with Euthasol (0.2 ml/kg, i.p.) 24 hours after the last injection of MK-801 or saline. The rats were rapidly perfused with ice-cold (< 4°C) sucrose solution filled with 95% O2 and 5% CO2 and then were decapitated. The sucrose solution contained (in mM) NaCl 87; KCl 2.5; NaH2PO4 1.25; NaHCO3 25; CaCl2 0.5; MgSO4 7.0; sucrose 75; and glucose 25. The brains were quickly removed and immersed in ice-cold sucrose solution. The frontal cortex was cut into 300-μm slices with a Leica Vibratome (VT 1000S; Leica, Bannockburn, IL), and the brain slices were incubated in oxygenated sucrose solution at 35°C for 1 hour. The cortical slices were kept at room temperature until being transferred into a submerged chamber for recording. The recording chamber was perfused with Ringer's solution bubbled with 95% O2 and 5% CO2 at a perfusion rate of 2 to 3 ml/minute. The Ringer's solution contained (in mM) NaCl 128; KCl 2.5; NaH2PO4 1.25; CaCl2 2; MgSO4 1.0; NaHCO3 26; and dextrose 10.
Whole-cell patch clamp recordings were conducted in the prelimbic region through an upright microscope (Olympus BX51WI, Olympus Optics, Japan) equipped with infrared-differential interference contrast optics. The recordings were conducted at ~35°C, and the resistance of the recording pipette (1.2 mm borosilicate glass, Warner Instruments Inc., Hamden, CT) was 4.5 to 7 MΩ. As we recently reported (Wang and Gao, 2009, 2010), the pipette tips were first filled with a K+-gluconate-based intracellular solution and then back-filled with Cs+-containing solution. The K+-gluconate solution contained (in mM) K+-gluconate 120; KCl 6; ATP-Mg 4; Na2GTP 0.3; EGTA 0.1; Hepes 10; and 0.3% biocytin (pH 7.3), whereas the Cs+-solution contained (in mM) Cs-gluconate 120; lidocaine 5 (QX-314); CsCl2 6; ATP-Mg 1; Na2GTP 0.2; Hepes 10; and 0.3% biocytin (pH 7.3, adjusted with CsOH). With this method, we were able to successfully record the action potentials (AP) immediately after forming a giga-seal. The membrane potentials were corrected for liquid junction potential (9.8 mV) of the K+-gluconate solution.
To record the miniature excitatory postsynaptic currents (mEPSCs), we stabilized the neurons in regular Ringer's solution for 5 minutes to allow the Cs+ diffusion into the neurons, and the spontaneous synaptic currents were continuously recorded for 5 minutes at a holding potential of −70 mV in the presence of picrotoxin (PTX; 50 μM, Sigma-Aldrich, St. Louis, MO) to block GABAergic transmissions. The mEPSCs were then recorded with the addition of tetrodotoxin (TTX, 1 μM, Ascent Scientific, Princeton, NJ) to block spontaneous action potential-induced synaptic currents. Twenty rats were used for this study. In one set of experiment (n = 8 rats), we recorded mEPSCs in pyramidal cells with 1 mM MK-801 loaded into recording pipette to block postsynaptic NMDA receptors; whereas in another group of rats (n = 10 rats), we examined mEPSC changes and spike properties following a single MK801 (0.1 mg/kg, i.p.) treatment. In some neurons, selective NR2B antagonist ifenprodil (3 μM) were bath-applied to examine the effects on mEPSC amplitude and frequency, which would reflect the subunit components of presynaptic NMDA receptors.
The evoked EPSCs were recorded in layer II/III neurons of the PFC by stimulating layer II/III with a bipolar electrode placed ~300 μm away from the recorded cells. To examine presynaptic NMDA receptors, we first applied paired-pulse (0.1 ms, 10–100 μA, 0.1 Hz, inter-stimulus interval 50 ms) to evaluate paired-pulse ratio (PPR) changes before (pre-AP5) and after AP5 treatment (n = 9 rats). In addition, we also we induced EPSCs with minimal stimulation which produced about 50% failures in all stimulus trials to observe the changes of percent failures after AP5 treatment (n = 6 rats).
To examine the AMPA receptor subunit changes in MK-801 model, we calculated rectification index (RI) as recently reported (Wang and Gao, 2010). A single pulse (0.1 ms, 10−100 μA, 0.1 Hz) was applied for the extracellular stimulation. The current-voltage (I–V) curve of the AMPA receptor-mediated EPSCs was determined by recording at −60, 0, and +60 mV in Ringer's solution containing PTX and the NMDA receptor antagonist AP5 (50 μM, Tocris Bioscience, Ellisville, MO) (n=32 rats).
In addition, in one set of experiment (n = 6 rats), the recorded neurons were clamped at -70 mV and bathed with PTX and AP5 to isolate AMPA receptor-mediated current. Then calcium permeable AMPA receptor (CP-AMPAR) antagonist 1-naphthylacetyl spermine trihydrochloride (NASPM, 50 μM) was bath-applied to examine the changes in AMPA receptor-mediated currents in MK-801 model.
To investigate the Ca2+ permeability of AMPA receptor-mediated currents in MK-801 model, the normal Ringer's solution containing 2 mM Ca2+ was replaced with a solution containing 30 mM Ca2+. The control (2 mM Ca2+) and highly concentrated Ca2+ (30 mM) solutions were identical in composition except for the concentrations of CaCl2 and NaCl, which (in mM) were 2 and 124 and 30 and 92.7, respectively. The evoked AMPA-EPSCs were first recorded in the control solution and then in the high-concentration Ca2+ solution for 10 min in the presence of PTX (50 μM) (n = 8 rats).
All electric signals were recorded with a MultiClamp 700B (Molecular Devices, Union City, CA) and acquired at sampling intervals of 20 to 50 μs through a DigiData 1322A and pCLAMP 9.2 software (Molecular Devices). The access resistances were constantly monitored through a pulse of negative 5 mV (200 ms duration) and were adjusted during recordings as needed.
The passive membrane properties in pyramidal cells and FS interneurons were measured as reported in our previous studies (Wang and Gao, 2009, 2010). These parameters included resting membrane potential, input resistance, membrane time constant, AP threshold, AP half-width, and afterhyperpolarization (AHP). The fast AHP and late AHP were analyzed on the basis of a previous report (Storm, 1987). The value of fast AHP was determined as the difference between the AP threshold and the lowest point of the first undershoot of the spike, whereas the late AHP was the second deep valley after the spike.
The mEPSCs recorded in the voltage-clamp mode were analyzed with Clampfit 9.2. A typical mEPSC was selected to create a sample template for event detection within a data period, and the AMPA mEPSCs were detected with a threshold set at three times the value of the root mean square of the baseline noise. The event numbers were sorted to make histogram at bin size of 2 pA and the data were fitted with Gaussian function in Clampfit 9.2. The rectification index (RI) of the evoked AMPA-EPSCs was calculated as the amplitude of AMPA-EPSC+60 mV/AMPA-EPSC−60 mV in the extracellular stimulus recording.
For all experiments, treatment effects were statistically analyzed by one-way ANOVA, followed by the appropriate post hoc tests using the software SPSS 16.0. Paired Student's t test was used when comparisons were restricted to two means in the neuronal samples (e.g., pre-AP5 and AP5), whereas unpaired nonparametric tests (Mann–Whitney) were used to compare the medians of two groups of nonparameter samples (i.e., the spike numbers). The Kolmogorov-Smirnov (K–S) analysis was applied to analyze the amplitude and interevent interval of mEPSCs. Error probability of p < 0.05 was considered to be statistically significant, and the data were presented as mean ± standard error.
Previous studies have indicated that treatment with a single dose of MK-801 induces significant changes in the firing properties of APs in the prefrontal cortical neurons in freely moving animals (Homayoun and Moghaddam, 2007; Jackson et al., 2004) and acute MK-801 produces opposite effects on pyramidal neurons and GABAergic interneurons (Homayoun and Moghaddam, 2007). In addition, we recently reported that pyramidal cells and FS interneurons in the PFC exhibit different subtypes of NMDA receptors (Wang and Gao, 2009; Wang et al., 2008b; Xi et al., 2009a). Notably, individuals that use NMDAR antagonist repeatedly, rather than acutely, display hypofrontality in functional imaging studies (Jentsch and Roth, 1999; Jentsch et al., 1997c; Pratt et al., 2008). Furthermore, the symptoms related to schizophrenia are more severe and enduring than after acute treatment with PCP in rats (Gilmour et al., 2011; Pratt et al., 2008). This suggests a dissociation of the acute and chronic effects of NMDA receptor antagonism on brain mechanisms particularly in relation to PFC activity and cognitive deficits (Gilmour et al., 2011; Pratt et al., 2008). We therefore wondered whether subchronic treatment with MK-801 would cause differential changes of membrane properties in the prefrontal neurons. All recordings were carried out in layer II/III of the medial PFC, and the morphological characteristics of all recorded cells were initially identified under infrared-differential interference contrast optics visualization. Pyramidal neurons showed cone-shaped soma and typical apical dendrites toward cortical layer I, whereas FS interneurons had round, oval, or elongated somas. These two kinds of neurons can also be distinguished by their distinctly different firing patterns that were immediately (< 1 min) recorded with step currents after the giga-seal formation in the patch-clamp recordings (Fig. 1A). The pyramidal neurons in both the vehicle control and the MK-801 model responded to the injection of the depolarizing somatic current with regular and frequency-adapting action potentials whereas FS interneurons were characterized by high-frequency fast firing without adaptation. No spontaneous firings were observed at the resting conditions in either the FS interneurons or the pyramidal neurons in the control, but spontaneous firing occurred in the MK-801 model in both cell types under resting conditions. The spike (AP) numbers of pyramidal neurons and FS interneurons in the MK-801-treated rats were not significantly different overall compared with those from the saline vehicle controls (two-way ANOVA: n = 7; F = 0.975, p = 0.448 for pyramidal cells; n = 5, F = 1.022, p = 0.427; Fig. 1B). The input resistances were significantly increased (p < 0.05) in pyramidal cells but not in FS interneurons (p > 0.05) compared with those in vehicle control cells. As shown in Table 1 and Figure 1C, the resting membrane potentials of both pyramidal neurons and FS interneurons were significantly depolarized in the MK-801 model (p < 0.005 for both pyramidal cells and FS interneurons). Two-way ANOVA analysis indicated that the membrane potential changes in MK 801 model were significantly different in both pyramidal cells and FS interneurons at current steps from −300 pA to +50 pA compared with those in saline controls (P: n = 7 for both control and MK 801, F = 4.764, p < 0.001; FS: n = 5 for both control and MK 801, F = 2.943, p < 0.01; Fig. 1C). The membrane time constant and AP half-width of pyramidal neurons in MK-801 model exhibited no significant changes compared with those in the controls. In contrast, the membrane time constant of FS interneurons decreased (p < 0.005) whereas the AP half-width of FS cells in the MK-801 model significantly increased compared with those in the controls (p = 0.001). Nevertheless, the patch-clamp recordings in both pyramidal cells and FS interneurons in the MK-801 model could last at least 30 min in most of the neurons recorded although the membrane properties were changed by treatment with MK-801.
To further explore the effects of MK-801 on the synaptic transmission, AMPA receptor-mediated mEPSCs were recorded from the pyramidal cells and FS interneurons under conditions of saline vehicle control and MK-801 treatment. The AMPA mEPSCs were pharmacologically isolated by bath application of the GABAA receptor antagonist PTX (50 μM) and the sodium channel blocker TTX (1 μM) at a holding potential of -70 mV. The mEPSCs were detected as fast inward currents (Fig. 2A) and could be completely blocked by the AMPA receptor antagonist DNQX (20 μM, data not shown). The basic properties of the AMPA mEPSCs in both FS interneurons and pyramidal neurons, including the rise time (p > 0.05 for both pyramidal cells and FS interneurons) and the decay kinetics (see scaled overlaps in Fig. 2B, p > 0.05 for both pyramidal cells and FS interneurons), exhibited no significant differences. However, both mEPSC amplitude and frequency recorded from the pyramidal cells were significantly increased in the MK-801 model compared with those in the controls (n = 9 for both control and MK-801, p < 0.05 for amplitude and p < 0.01 for frequency; Fig. 2B–D left panels). In contrast, in the FS interneurons, the mEPSCs amplitude was significantly decreased by about 50% (19.1 ± 2.10 pA in control vs. 9.30 ± 0.85 pA in MK-801, n = 7 for both, p < 0.001; Fig. 2C right panel), whereas the interevent intervals (frequency) of the mEPSCs were not significantly changed although there was a tendency of decrease in MK-801 model (p > 0.05; Fig. 2D right panel) compared with those in the vehicle control. It should be noted that the frequency change could also derive from changes in postsynaptic AMPA receptors. Because MK-801 induced significant changes of membrane properties in FS interneurons, it is possible that the synaptic efficacy was altered in FS interneurons, as shown in Figure 2B (right panel). The decreased amplitude of the mEPSCs suggested a possible postsynaptic hypofunction of AMPA receptors, whereas the unchanged frequency of mEPSCs might be attributable to an unaltered presynaptic glutamate release. These results suggest that FS interneurons were indeed in the state of hypofunction, whereas pyramidal neurons were altered with an increased release of glutamate and postsynaptic AMPA receptor-mediated activity in the MK-801 model, as previously proposed (Javitt, 2004; Lisman et al., 2008; Millan, 2005; Moghaddam and Jackson, 2003; Olney and Farber, 1995).
To examine whether there are similar changes after a single MK-801 treatment, we recorded mEPSCs in both pyramidal neurons and FS interneurons 24 hours after a single injection of MK-801 (n = 9 rats at PD30–39) compared with those in 5-day injection. As shown in Supplemental Figure 1, we found that, interestingly, there are no significant differences in both mEPSC amplitude and frequency in either pyramidal neurons or FS interneurons. This result suggests that even single injection of MK-801 could induce clear alteration in AMPA receptors in the prefrontal neurons.
This raises question of whether single challenge with MK801 also induces changes in intrinsic membrane properties and firing characteristics as exhibited in Table 1. However, as shown in the Supplemental Table 1, single injection of MK-801 did not alter the somatic membrane properties in both pyramidal cells and FS interneurons in the rat PFC despite the significant effects on the axonal terminals (see Supplemental Figure 1). This result suggests that repeated subchronic treatment with MK-801 induced more severe impairments in the prefrontal neurons than with single injection.
Presynaptic NMDA receptors enhances glutamate release and thus increases the frequency of mEPSCs in the entorhinal cortex (Berretta and Jones, 1996; Woodhall et al., 2001; Yang et al., 2006), visual cortex (Sjostrom et al., 2003), and dentate gyrus (Jourdain et al., 2007). Although presynaptic NMDA receptors were reported in the entorhinal cortex in adult animals (Woodhall et al., 2001; Yang et al., 2006), it has also been reported that presynaptic NMDA receptors are gradually lost during cortical development (Corlew et al., 2008; Mathew and Hablitz, 2011). Whether presynaptic NMDA receptors exist in axon terminals targeted on pyramidal cells and FS interneurons in the adolescent rat PFC is unknown. In addition, because MK-801 could potentially block both pre- and postsynaptic NMDA receptors in a use- and activity-dependent manner, we tested whether the altered glutamate release and postsynaptic AMPA receptor-mediated mEPSCs were attributable to the changes in presynaptic NMDA receptors in both pyramidal cells and FS interneurons.
We first examined whether presynaptic NMDA receptors exist in the excitatory synaptic terminals connected to layer II/III pyramidal neurons in the mPFC. To examine the presynaptic NMDA receptors, paired-pulse stimulation was employed with interpulse interval of 50 ms (20 Hz) and stimulus frequency at 0.1 Hz (every 10 seconds). The intracellular solution containing MK-801 (1 mM) was applied to block the postsynaptic NMDA receptors, as described in previous study (Mathew and Hablitz, 2011; Sjostrom et al., 2003). The evoked AMPA receptor-mediated EPSCs were continuously recorded at a holding potential of −70 mV in the presence of PTX (50 μM) and GABAB receptor antagonist CGP55845 (1 μM, Tocris Bioscience, Ellisville, MO). The EPSCs were recorded with input resistance and holding current of the neurons being continuously documented. After 10 min baseline recording, AP5 (50 μM) was added into the bathing solution and the neurons were recorded for another 10 min. The data recorded from the second 5 min in both baseline and AP5 were used for analysis and statistic comparison. The paired-pulse ratio (PPR) was determined as the peak amplitudes of EPSC2/EPSC1. As shown in Figure 3A and B, paired-pulse facilitations were usually observed in the baseline in 11 out of 15 neurons recorded. In contrast, bath application of AP5 significantly decreased the PPR by 26.7 ± 3.56 % (n = 15, p < 0.0001; Fig 3A,B) and the 2nd EPSC amplitudes without alterations in either input resistance or holding current (Fig. 3A).
To further confirm the existence of presynaptic NMDA receptors, we recorded evoked EPSCs in pyramidal neurons at −70 mV in the presence GABAA receptor antagonist PTX (50 μM) and AP5 (50 μM) with minimal stimulation. We calculated the percent changes of synaptic failures before and after AP5 application (Fig. 3C). We found that AP5 wash-in significantly decreased the EPSC amplitude from 17.7 ± 4.09 pA to 11.0 ± 2.97 pA (n = 6, p = 0.014) and increased the synaptic failure from 50.0 ± 7.30% to 72.5 ± 8.64% (n = 6, p = 0.012; Fig. 3D). These data confirm the presence of presynaptic NMDA receptors in the adolescent rat prefrontal cortical neurons.
Next, we tested whether the mEPSC amplitude changes induced by chronic MK-801 treatment (shown in Fig. 2) were associated with alterations in presynaptic NMDA receptors. The mEPSC recordings were carried out with bath solution containing TTX (1 μM) and PTX (50 μM) in both the vehicle control and MK-801-treated group. The membrane potentials of the pyramidal neurons were clamped at −70 mV during recordings. The mEPSCs were recorded for 10 min as the baseline (pre-AP5), and then AP5 (50 μM) was administered to block presynaptic NMDA receptors; mEPSCs were continuously recorded for another 10 min. The AMPA mEPSCs could act as activity reporters of presynaptic NMDA receptors under this condition because the role of postsynaptic NMDA receptors in the AMPA mEPSCs is negligible under such a condition (Rotaru et al., 2011; Sjostrom et al., 2003). As shown in Figure 4, we found that the frequencies of the mEPSCs were significantly reduced by application of AP5 in both the controls and the MK-801 model (Fig. 4A), whereas the average amplitudes of mEPSCs were not altered by AP5 administration in the neurons treated with MK-801 (p > 0.05, n = 9; Fig. 4B, C). K–S analysis of the cumulative probability distributions of interevent interval showed significant increases after treatment with AP5 (p < 0.001, n = 9 for both vehicle control and MK-801 group; Fig. 4D). Indeed, the average frequency of mEPSCs in the vehicle control decreased from 0.67 ± 0.17 Hz to 0.42 ± 0.12 Hz after AP5 (p < 0.05, n = 9), whereas the frequency in the MK-801 model decreased from 2.24 ± 0.46 Hz to 0.57 ± 0.15 Hz (p < 0.01, n = 9; Fig. 4E). It is interesting that both the mEPSC amplitude (9.33 ± 0.67 pA in control vs. 13.11 ± 1.36 pA in MK-801, n = 9; p < 0.05) and frequency (0.67 ± 0.17 Hz in control vs. 2.24 ± 0.46 Hz in MK-801, n = 9; p < 0.01) in the MK-801 model were significantly higher than those in the vehicle control under the pre-AP5 conditions (Fig. 4C, E), suggesting an increased presynaptic release and/or postsynaptic AMPA receptor-mediated scaling that are affected by presynaptic NMDA receptors. This conclusion was further supported by displaying the data in histogram which was created with the mEPSC event numbers at a bin size of 2 pA. The amplitude histograms of mEPSC events also exhibited significant decreases by AP5 administration in both vehicle control and MK801 model (Fig. 4F, G). These data indicated that MK-801 treatment induced new additions of presynaptic NMDA receptors to the axon terminals targeting the pyramidal neurons.
Previous study indicated that MK-801 reached maximal concentrations in plasma and brain within 10 to 30 min of injection (2 mg/kg) with an elimination half-life of 1.9 and 2.05 hours, respectively (Vezzani et al., 1989). Because concentration-time curve in brain area is significantly longer than the concentration-time curve in plasma (Vezzani et al., 1989), it is possible that there is remaining MK-801 which might be still effective but not sufficient to block all NMDA receptors after 24 hours. To confirm the presence and function of presynaptic NMDA receptors and to exclude the effects of postsynaptic NMDA receptors, we recorded mEPSCs in pyramidal cells with 1 mM MK-801 loaded into pipette solution in subchronic MK-801-treated rats. We found that mEPSC amplitude was not affected by AP5 application (12.4 ± 1.58 pA for pre-AP5 versus 11.4 ± 1.50 pA for AP5; n = 9, p = 0.119) but the mEPSC frequency was significantly decreased by AP5 (1.83 ± 0.48 Hz for pre-AP5 versus 1.11 ± 0.38 Hz for AP5; n = 9, p = 0.017; Fig. 4H). Further analysis with coefficient of variation (CV) of the mEPSCs projected a reduced CV after AP5 application because the average ratio (AP5/pre-AP5) of CV2 was about 0.7 and located below the horizontal line in the lower half quadrant in the MK-801 model (Fig. 4I) (Gray et al., 2011). This analysis indicates that AP5 directly reduced the presynaptic release probability as postsynaptic NMDA receptors were blocked by loaded MK-801 loaded in the pipette. The trend of changes was similar to those exhibited in Figure 4C, E and G. These data confirmed MK-801's effect on the newly inserted presynaptic NMDA receptors in the glutamatergic terminals targeting pyramidal neurons.
Whether presynaptic NMDA receptors exist in axon terminals targeted on FS interneurons in the PFC is unknown. Thus, we examined the presynaptic NMDA receptors on FS interneurons. Similarly, the membrane potentials of the FS interneurons were clamped at -70 mV during recordings and the bath solution contained TTX (1 μM) and PTX (50 μM). The mEPSCs were recorded for 10 min as the baseline (pre-AP5), followed by AP5 (50 μM) administration for another 10 min. In the cells recorded in the vehicle control rats, the average amplitude of mEPSCs exhibited no significant changes in response to AP5 administration (p > 0.05, n = 7; Fig 5A–C), whereas the interevent interval increased significantly (p < 0.0001, n = 7), indicating a significant decrease of the mEPSC frequency (1.17 ± 0.37 Hz in pre-AP5 vs. 0.56 ± 0.16 Hz in AP5, n = 7, p < 0.05; Fig. 5D, E). As exhibited in Figure 5F, the mEPSCs events were markedly decreased by AP5 administration in the neurons recorded from the vehicle control. These data suggested that presynaptic NMDA receptors are still distributed in the glutamatergic axon terminals targeted on FS interneurons in the normal adolescent rat PFC. In contrast to the vehicle control, neither the average amplitude (p > 0.05, n = 7) nor the frequency (p > 0.05, n = 7) of the mEPSCs between pre-AP5 and AP5 treatment was changed in the MK-801 model (Fig. 5B, C, E, G). These data indicate that MK-801 blocked the existing presynaptic NMDA receptors in the axon terminals targeted on FS interneurons and that the blockade was long-lasting without recovery and new insertion even after 24 hours of MK-801 administration.
We further identified the subunit components of NMDA receptors in the presynaptic axonal terminals targeting on pyramidal cells and FS interneurons 24 hours after a single injection of MK-801 (0.1 mg/kg, i.p.) in four rats (aged PD40–44, n = 4). As shown in Supplemental Figure 2, we recorded mEPSCs in both pyramidal neurons (n = 7) and FS interneurons (n = 6) with intracelluar solution containing 1 mM MK-801 (at a holding potential of −70 mV) in the presence of 50 μM PTX and 1 μM TTX. We found that ifenprodil had no effects on the mEPSC amplitudes in both pyramidal cells (p = 0.127) and FS interneurons (p = 0.432). However, ifenprodil significantly decreased mEPSC frequency by 33.8 ± 0.08% in pyramidal cells (p = 0.003) but had no clear effects on the mEPSC frequency in FS interneurons (p = 0.543). These results suggest that the NMDA receptor subunits in the presynaptic axonal terminals targeting on pyramidal cells and FS interneurons appear to be different, with more NR2B subunit in the axon terminals targeting on pyramidal cells than those on FS interneurons.
The calcium (Ca2+) permeability of AMPARs is critically dependent on GluR2 subunits. Those containing GluR2 are Ca2+ impermeable (CI-AMPAR) and have a linear current–voltage (I–V) relation, and those lacking GluR2 are Ca2+ permeable (CP-AMPAR) and are strongly inwardly rectifying (Hollmann and Heinemann, 1994; Jonas and Burnashev, 1995; Wang and Gao, 2010). GluR2-lacking CP-AMPARs have recently received considerable attention because of their postulated role in synaptic plasticity (Adesnik and Nicoll, 2007; Clem and Barth, 2006; Liu and Cull-Candy, 2000; Plant et al., 2006) and neurological disorders (Cull-Candy et al., 2006; Isaac et al., 2007; Liu et al., 2006; Liu and Zukin, 2007; Tanaka et al., 2000). We recently reported that most of the FS interneurons in the PFC express calcium-permeable AMPA receptors (CP-AMPA) during the adolescent period (Wang and Gao, 2010). We therefore wondered whether MK-801 treatment also affects the calcium permeability of AMPA receptors. To explore the changes in AMPA receptors in the MK-801 model, we plotted the I-V curve of the AMPA receptor-mediated EPSCs in both pyramidal neurons and FS interneurons. The AMPA receptor-mediated currents were recorded at membrane potentials held at −60, 0, and +60mV, respectively. The recorded neurons were bathed with normal Ringer's solution containing PTX (50 μM) and AP5 (50 μM), with spermine (50 μM) included in the intracellular solution (Wang and Gao, 2010). The currents were evoked by low-intensity stimulation of intracortical fibers with a bipolar electrode placed near the soma in layer II–III. The I–V curves of AMPA EPSCs in the FS interneuron and pyramidal cells are shown in Fig. 6A, and the RIs of EPSCs were calculated by the conductance ratios of EPSC+60mV/EPSC−60mV. It is known that cells expressing appreciable levels of GluR2, which form calcium-impermeable (CI)-AMPA receptors with linear or outwardly rectifying I-V relationships, were usually unaffected by the application of spermine. As reported in our recent study, the breakup value of RI was set at 0.7; the recorded pyramidal neurons and FS interneurons in the PFC of the vehicle control and the MK-801 can easily be identified as cells with CI- or CP-AMPA receptors. All of the pyramidal neurons examined (n = 7) showed as CI in the PFC in normal adolescent rats, consistent with the findings from a previous study (Kumar et al., 2002), whereas in the MK-801 model, the RI values in 7 of 8 pyramidal cells recorded were lower than 0.7, significantly deceased compared with those in the vehicle controls (RI = 1.50 ± 0.24 in control vs 0.47 ± 0.08 in MK-801, χ2 = 28.02, p < 0.001; Fig. 6A, B). Similarly, in the 20 FS interneurons recorded in the vehicle control, 14.3% primarily expressed CI− and 85.7% expressed CP-AMPA receptors, consistent with our recent report (Wang and Gao, 2010). In contrast, in the MK-801 model, all of the 12 FS interneurons tested exhibited CP-AMPA receptors. The RIs were significantly decreased in the MK-801-treated group compared with those in vehicle controls (RI = 0.36 ± 0.10 in control vs 0.30 ± 0.04 in MK-801, χ2 = 22.71, p < 0.0001, Fig. 6A, B). These results suggest that treatment with MK-801 induced clear changes in the AMPA receptor subunits and increased the CP-AMPA receptors in both pyramidal neurons and FS interneurons.
To confirm this finding, we conducted an additional experiment to examine the amplitude changes of AMPA receptor-mediated currents with bath application of CP-AMPARs antagonist NASPM in MK-801 model. The recorded neurons were clamped at −70 mV and bathed with 50 μM PTX and 50 μM AP5 to isolate AMPA currents. After the currents were stable, we recorded 5 minutes as baseline and then recorded another 10 minutes with additions of 50 μM NASPM, followed by washing out with ACSF containing PTX and AP5. In the normal control animals, the EPSC amplitude was not altered with NASPM application in pyramidal cells (n = 9, p = 0.240) but was significantly decreased by 20.8% in FS interneurons (n = 6, p = 0.036; Fig. 7A and B). These results suggested that FS interneurons, but not pyramidal cells, express CP-AMPA receptors in normal rat PFC during adolescent period, in support of our recent report (Wang and Gao, 2010). In contrast, in the MK-801 model, NASPM application significantly reduced the EPSC amplitude by more than 30% in pyramidal cells (n = 6, p = 0.0014) and about 42% in FS interneurons (n = 6, p = 0.011; Fig. 7A and B). The percent changes of EPSC amplitude in MK-801-treated neurons were significantly higher than those in the control for both pyramidal neurons and FS interneurons (p = 0.048 for pyramidal cells and p = 0.048 for FS interneurons). These results further confirmed that CP-AMPA receptors were indeed increased in both pyramidal neurons and FS interneurons in the MK-801-treated animals.
The significant increases in the CP-AMPA in both pyramidal neurons and FS interneurons in the MK-801-treated rats suggest a possible increase in Ca2+ permeability. To explore this possibility in the MK-801 model, we measured the peak amplitude values of AMPA-receptor-mediated EPSCs with neurons clamped at −60, 0, and +60 mV, respectively, as described above. The I–V relationships for synaptic responses of AMPA receptors were first recorded in normal Ringer's solution (2 mM Ca2+) in the presence of PTX (50 μM); then the Ringer's solution was replaced with a solution high in Ca2+ (30 mM). We found that after bathing with a 30-mM Ca2+ solution for 10 minutes, the RI values of the FS interneurons in the MK-801 model also decreased significantly (p < 0.05, n = 7), whereas the RI values in pyramidal cells were not significant from those in the control (p > 0.05, n = 5; Fig 8A, B). These data suggested that the synaptic AMPA receptors in the FS interneurons (but not in the pyramidal neurons) in the MK 801 model were altered to be more permeable to Ca2+influx, which may increase the vulnerability of FS interneurons to harmful stimulation.
To test the synaptic mechanisms of the NMDA hypofunction hypothesis for schizophrenia, we selectively examined the functional changes in AMPA and NMDA receptors in individually identified FS interneurons compared with those in pyramidal cells in the MK-801 model of adolescent rat PFC. We found that, although both pyramidal neurons and FS interneurons were impaired by a subchronic blockade of NMDA receptors, MK-801 induced several selective alterations in FS interneurons but not in pyramidal cells, including a significantly reduced RI and increased calcium permeability. In particular, MK-801 induced a significant decrease in the AMPA-mEPSC amplitude in FS interneurons but significant increase in both frequency and amplitude of AMPA-mEPSC in pyramidal neurons. In addition, presynaptic NMDA receptors in the axon terminals targeting FS interneurons were completely blocked without recovery whereas new presynaptic NMDA receptors were inserted into the glutamatergic terminals onto pyramidal neurons.
Numerous studies have reported NMDA receptor changes induced by administration of NMDA antagonists (Barbon et al., 2007; Gao and Tamminga, 1995; Harris et al., 2003; Lindahl and Keifer, 2004; Rujescu et al., 2006; Wang et al., 1999). There is, however, little consensus on the alterations in NMDA receptor subunits that might contribute to the NMDA hypofunction on the basis of the observations obtained from postmortem brains in patients with schizophrenia (Akbarian et al., 1996; Luthi et al., 2001; Matthews et al., 2000; Meador-Woodruff and Healy, 2000; Moghaddam, 2003). Nevertheless, these studies have provided strong evidence for the network effects of these compounds and established the theoretical basis for the NMDA hypofunction hypothesis for schizophrenia pathogenesis (Lisman et al., 2008). Despite the intriguing hypothesis of disinhibition based on the deficits of GABAergic transmission in the brains of patients with schizophrenia, little evidence is available showing how NMDA receptor antagonist affects the synaptic transmissions on the identified FS interneurons and how the alteration in synaptic transmission mechanistically elucidates the dysfunction of the network. We found that the AMPA mEPSCs were significantly and distinctly changed in the pyramidal cells and FS interneurons by the subchronic in vivo blockade of NMDA receptors with MK-801. Our data indicate that MK-801 induced the hypofunction of FS interneurons by both pre- and postsynaptic mechanisms. The increased amplitude of AMPA mEPSCs in the pyramidal neurons that we observed is consistent with the findings from several previous studies conducted in cultured hippocampal and cortical neurons (Kato et al., 2007; Sutton et al., 2006; Sutton et al., 2004; Turrigiano and Nelson, 2004). These studies showed that postsynaptic scaling in AMPA mEPSCs occurs after chronic blockade of NMDA receptors with AP5 (Kato et al., 2007; Sutton et al., 2006) or of neuronal activity with TTX (Sutton et al., 2006; Sutton et al., 2004; Turrigiano and Nelson, 2004). In addition, the frequency of AMPA mEPSCs in pyramidal neurons (but not FS interneurons) was significantly increased. In contrast, the amplitude (but not frequency) of AMPA mEPSCs in FS interneurons was significantly decreased, distinctly different from the changes in pyramidal neurons. Altogether, our data provide novel evidence of cell-type specific alterations of AMPA receptors, i.e., decreased excitatory response in FS interneurons (reduced AMPA current) and increased glutamate release and response in pyramidal neurons (increased frequency and amplitude of AMPA current). How could these happen? Target-specific expression of pre- and postsynaptic mechanisms of synaptic transmission has been shown in a variety of central neurons under by a number of laboratories (Bacci et al., 2005; Isaac et al., 2007; Toth and McBain, 2000), including our own studies in dopaminergic regulation (Gao and Goldman-Rakic, 2003; Gao et al., 2003) and MK-801 effects on NMDA receptors (Xi et al., 2009b). These data have demonstrated that synaptic transmission between single axons diverging onto distinct target neurons can behave independently, differentially influencing activity in the target neuron (Toth and McBain, 2000).
In addition, our data indicate that presynaptic NMDA receptors remain available in the axon terminals targeting on PFC layer II/III pyramidal neurons and FS interneurons in the normal adolescent animals, differing from previous studies reported in primary visual cortex (Corlew et al., 2008; Corlew et al., 2007) but were consistent with those findings in entorhinal cortex (Woodhall et al., 2001; Yang et al., 2006). Our data thus suggest a brain region difference for the development of presynaptic NMDA receptors. Presynaptic NMDA receptors are known to be critical to facilitate glutamate release and alterations of presynaptic receptors dramatically affect the neuronal and network activity (Bidoret et al., 2009; Brasier and Feldman, 2008; Corlew et al., 2008; Corlew et al., 2007; Rodriguez-Moreno and Paulsen, 2008). Indeed, we found that presynaptic NMDA receptors in the synaptic inputs onto pyramidal neurons and FS interneurons were differentially affected by MK-801 treatment, further support a cell-type specific action of MK-801. In the excitatory axonal terminals targeting onto FS interneurons, presynaptic NMDA receptors were completely blocked without recovery. In contrast, more presynaptic NMDA receptors were detected in the glutamatergic axonal terminals targeting pyramidal neurons. The blockade of presynaptic NMDA receptors in the excitatory inputs onto FS interneurons could significantly reduce glutamate release in the synapses distributed on these cells and thus cause a reduced inhibition because AMPA receptors play a critical role in the regulation of FS interneuron functions (Rotaru et al., 2011). The reduced excitatory drive in FS interneurons and the increased excitation in pyramidal neurons will consequently change the excitation-inhibition balance, which could eventually cause over-excitation in pyramidal neurons, excessive glutamate release, and even excitotoxicity in the limbic regions, as proposed in the hypothesis of NMDA hypofunction (Lisman et al., 2008; Olney and Farber, 1995).
Another major finding in our study is the differential changes in postsynaptic AMPA receptors on FS interneurons and pyramidal cells. We found that in the MK-801 model, the RIs in both pyramidal neurons and FS interneurons were significantly decreased, indicating a clear change in AMPA receptor subunits (i.e., GluR1 or GluR2). This result was consistent with that of a previous study in cultured neurons in which NMDA blockade enhanced the synthesis and surface expression of GluR1 but not of GluR2 subunits (Sutton et al., 2006). It is possible that a high concentration of glutamate accumulated in the synaptic cleft lead to the downregulation of GluR2 (Barbon et al., 2007) or upregulation of GluR1 (Sutton et al., 2006). Although it remains unclear whether the changes in RIs induced by treatment with MK-801 in vivo were attributable to the alteration of GluR1 or GluR2 subunits, the decreases in RIs suggest an increase of CP-AMPA receptors and possibly the increase of calcium permeability as well. Indeed, our data suggest that the calcium permeability significantly increased in FS interneurons. Further biochemical study is needed to determine the changes in AMPA receptor subunits and the associated mechanisms on how blockade of NMDA receptors induces the changes in AMPA receptor subunits. Nevertheless, because of the distinct physiological properties, FS interneurons expressing CP-AMPARs may play different roles in integrating neuronal information within the prefrontal cortical circuit during normal and pathophysiological activities (Isaac et al., 2007; Wang and Gao, 2010). They also show distinct vulnerability to disruptive influences such as NMDA receptor antagonists and other agents associated with Ca2+ influx due to high Ca2+ permeability. Therefore, the MK-801-induced increase of CP-AMPARs in FS interneurons may make these cells particularly vulnerable to disruptive influences in the PFC, which may explain the selective impairment of GABAergic interneurons, particularly FS interneurons in the MK-801 (Paulson et al., 2003; Simpson et al., 2010) and PCP model (Pratt et al., 2008; Schroeder et al., 2000).
An important question is whether the consequences of repeated dosing with NMDAR antagonists offer a model of schizophrenia with validity and/or practical utility. Numerous studies indicated that, in the rodent and monkey PFC, repeated rather than acute treatment with NMDAR antagonists resembles the neuroanatomical and neurochemical changes observed in schizophrenics more closely (Abdul-Monim et al., 2006; Amitai and Markou, 2009; Amitai et al., 2007; Ashby et al., 2010; Cochran et al., 2003; Enomoto et al., 2005; Hajszan et al., 2006; Jentsch et al., 1997a; Jentsch et al., 1997b; Mandillo et al., 2003; Murai et al., 2007; Paulson et al., 2003; Rasmussen et al., 2007; Reynolds et al., 2004; Rujescu et al., 2006; Simpson et al., 2010), although not all work is in agreement here (Cochran et al., 2003; van Elst et al., 2005). Our recent studies have also suggested that subchronic administration of MK-801 induces significant alterations in NMDA receptors (Xi et al., 2009b) and these changes can be efficiently reversed by treatment with group II mGluR 2/3 agonist (Xi et al., 2011). However, it should be noted that although subchronic administration of NMDA receptor antagonists are more effective than acute application, adverse effects in this treatment are also obvious. In the present study, we observed significant changes in the passive membrane properties (Table 1). These are probably corresponding to physiological changes in the synapses or ion channels distributed in the neuronal dendrites, as previous study reported (Hajszan et al., 2006). It is also possible that these changes are derived from the drug's excitotoxic effects. For example, subchronic MK801 injection caused a large depolarizing shift in membrane potential, a decrease in the membrane time constant, and an increase in the action potential half-width in FS interneurons. These changes suggest that ionic channels open at rest and during action potential generation are different between control and MK801 injected animals. A decrease in the membrane time constant is consistent with a possible dendritic degeneration (Isokawa, 1997). Also, the significant decrease in mEPSC amplitudes in FS interneurons (Figure 2) suggested a possible loss in the number of synapses (Hajszan et al., 2006). These changes could explain the impaired cognitive deficits induced by low-dose subchronic treatment with MK-801 in adolescent rats (Li et al., 2011) and thus support the validity of the subchronic MK-801 model in addressing important issues in the schizophrenia research (Gilmour et al., 2011).
In summary, our data suggest a distinct cell-type specific and homeostatic synaptic scaling and redistribution of AMPA and NMDA receptors in response to the subchronic blockade of NMDA receptors and provide a direct mechanistic explanation for the NMDA hypofunction hypothesis that have long been proposed in the NMDA receptor antagonist model.
We thank Dr. Melissa A. Snyder for comments on the manuscript and Pamela Fried in the DUCOM academic publishing services for editorial work.
Funding sources
This study was supported by a grant from National Institutes of Health (NIH) R21 grant MH232307 and R01 MH232395 to W-J Gao. The NIH had no further role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication.
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text: with the new Facebook update i was delighted that they added inbox support but this feature isn't woking as it should.... when i sent more than 30 or so messages to one person (in the same thread of messages) i cant read the most reacent ones that i receive... it simply wont scroll down far enough to let me read them but will stop scrolling down at earlier messages which i have already replied to. however it does tell me that i have received a message through a notification and when i go on the computer their is a message. so is their anyway of fixing this or do i have to start a new thread of messages every time i go over 30ish messages? i have a htc legend with the latest version of facebook v1.2


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Drive Home in a New Acura TLX, MDX, RDX or ILX From Acura Of Concord
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You've fallen in love with your new Acura and you've invested a lot in it. Of course you're going to want to take the best possible care of it. Here at Acura of Concord we appreciate the excellence of the Acura brand and we are committed to providing top-quality care for your vehicle, so you can feel confident visiting our auto service center for any of your needs. Whether it's a simple oil change or a bigger repair, we always use genuine Acura parts to keep your vehicle running at optimum performance. It's just one more reason that Oakland, Danville, Walnut Creek, and Pleasant Hill drivers love our Acura experts in Concord.


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THERE are no half-measures about Marseilles, a place so different in so many ways from the other great cities of France that you almost feel a visa might be required for a visit. Paris, Lyons, Bordeaux seem pale and tame by comparison: there's a distinct whiff of sulphur about this raw, racy metropolis, bubbling with a rich stew of organised crime, official corruption and social tensions.
As a consequence, outsiders can find Marseilles rather intimidating: Parisians will warn you, only half-joking, to keep your hand on your wallet and sit facing the door. Sometimes the Marseillaises cannot resist playing up to this, putting on the French Connection style and swagger for out-of-towners, ushering them around bars and pizza parlours where gangland scores have been settled with a shotgun blast.
Warm and welcoming to those who make the effort to get to know their beloved city, they are quick to take offence at anyone they suspect of patronising them. "We've had a gut full of self-styled experts telling us everything that's wrong with Marseilles," snaps a local journalist. "If that makes us a bit épineux, prickly, well then, you can take us or leave us."
More than anything, the Marseillaises like to show two fingers to the Parigots, an anything but affectionate nickname for the frosty inhabitants of the capital far away in the north (which begins, locals insist, around Avignon).
This explains why there is now such a head of steam building up locally for the celebrations not of the looming Millennium but of the 2,600th anniversary of Massilia, founded by the Phoenicians when Paris was still a collection of mud huts.
The man in charge of planning this momentous event is the affable Serge Botey, temporarily detatched from his job as a librarian and, like all good Marseillaises, not shy about proclaiming his city's singular charms. As Botey observes, the 1998 World Cup provided a heaven-sent opportunity to show visitors from around the globe what it had to offer, on and off the pitch, and by most accounts, it did them proud.
"We now have a wonderful chance to keep that momentum going with the 26th-century fête," Botey says. "Nowhere else in France do people have a stronger sense of history and identity than here, and that's what makes us special." I wouldn't dispute it: working as a journalist in Paris, I always looked forward to assignments - underworld slayings, baroque civic scandals and the occasional race riot - that took me to Marseilles.
Cut off from the "interior" (a term of disdain for locals) by a palisade of parched white hills, sprawling along the Mediterranean coastline through unlovely industrial zones for the best part of 30 miles, it has absolutely nothing in common with the Provence of smart seaside resorts away to the east.
My first stop those days was usually a dark café off the Quai des Belges, the stretch of the Old Port lined with tourist bars and brasseries, where off-duty cops would line up their pastis of an evening. The police chief then was an exceedingly tough man of Vietnamese origin, George 'N Guyen Van Loc. He once walked me along the Quai, pointing out, in the penetrating Marseilles accent that the rest of France finds so comical, the more colourful of his "clients".
A hulking, dramatically scarred bruiser drinking beer on a shady terrace was the minder of a notorious mobster who specialised in hijacking security vans. The well-dressed woman carefully selecting her dinner from trays of fish so fresh that they were still twitching was the madame of a flourishing stable of whores. A lawyer scurrying by in court robes, splash of white lace at his collar, was the defending maître of choice for crooked politicians.
The latter part of the 20th century has not been particularly kind to Marseilles: high long-term unemployment from the loss of traditional industries and the decline of the great port and its theft-ridden docks. Ugly tensions focused on the large immigrant population - most of North African origin - have provided fertile ground for the National Front.
For a while during the late Eighties and early Nineties, the city seemed to have lost its way: behind the languorous façade of boules in shady parks, leisurely dinners of bouillabaisse and promenades in the stunning evening light, one sensed a communal ebbing of confidence.
But Marseilles has a long, proud history of overcoming adversity, from medieval plagues and raids by British naval fleets to revolutionary turmoil - La Marseillaise was first sung in battle by local troops - and a destructive German occupation during the Second World War. And little by little, the city recovered its nerve, rediscovered its Mediterranean vitality and gruff good humour. Nobody pretends that the social problems in the quartiers sensibles - the squalid estates where many immigrants live - have gone away, but the significant decline of the National Front vote in recent local elections is, at the least, a sign of hope.
Ask Serge Botey about the concrete jungles in the northern suburbs and he adeptly switches track: yes of course, these Sixties blocks, thrown up in a rush to accommodate the immigrant influx, are pretty grim. But kindly remember, he says, that it was on these same slopes, running down to the sea, that Cézanne used to paint landscapes. For Botey, the corniche winding east from the Old Port towards the best beaches is a splendid "balcony over the Mediterranean"; the quartier of Goudes is "a true marriage between the Homeric Greece of Carthage and Provence".
My own idea of the perfect lazy day begins on a fishing boat to one of the calanques, the narrow creeks that riddle the coastline on either side of the city. For generations, the Marseillaises have come out here to recharge their batteries in weekend cabins.
The more popular calanques usually have a restaurant at hand, and the odours of traditional Provençal cuisine hang in the air - aioli, grilled sardines, fish soup - as carafes of icy local rosé accumulate on the crowded tables. The hours slip by unnoticed in fiercely competitive rounds of boules, raucous card schools, swimming and idle chatter.
There will always be animated discussion of the fortunes of "l'OM", the city's cherished football club, Olympique de Marseille, currently celebrating its 100th anniversary. Matches at the magnificent 60,000-seater Vélodrome stadium generate phenomenal passion, above all when the visitors are Paris-St-Germain. OM fans can be capricious, but once they take a player to their heart - whether he's a hometown boy or an expensive import - it's a true love affair.
The city's temperament seems to breed the need for local heroes: the disgraced financier/politician Bernard Tapie, former owner of OM, was worshipped before his downfall. When the Socialist mayor, Gaston "The Rock" Deferre - patrician Resistance leader, duellist and power-broker supreme - died in the mid-Eighties after more than 30 years in office, black-bordered newspaper headlines announced "Marseilles Orphaned".
Marseilles is charging towards its 26th centenary with every intention of upstaging the rest of France. The new prefect of police, Hugues Parent, wants the world to know that the city now ranks 49th in the league table of crime for France's larger population centres: as the former head of France's tourist authority, he understands the importance of making visitors feel secure.
But Parent is quite right to argue that it is vital for Marseilles to preserve what he neatly defines as la mixité of its inhabitants - the blend of rough and smooth - especially in and around La Canebière, the broad avenue that divides the city centre. If the surge of modern office and shopping developments there reflects a new economic dynamism, the casbah-style sidewalk stalls and street hawkers serve as a reminder that Marseilles once lived off trade with the French colonies in Africa and the Orient (in the early 19th century, Stendhal visited a local bordello whose rooms were each named for a different Eastern city).
Since tourist guides occasionally come unstuck with recommendations for Marseilles, I will say only that I have never been disappointed by the Sofitel Vieux Port, with its superb view of the harbour; never had a bad meal at Chez Aldo (fish straight from the boat, try for a terrace table); and never tired of leaning on the bar of the New York brasserie on the Quai des Belges and watching smart Marseillaises rub shoulders with an agreeably raffish crowd from the other side of the tracks.
Not long ago, I caught a late-afternoon flight out of Marseilles and was treated to the sight of the entire city below bathed in a glowing soft light that transformed even the ugliest of the high-rise housing blocks. It reminded me of something I had read recently: that Marseilles resembles an elusive seductress who reveals her true beauty only to those who most deserve it.
Getting there
Air France (08450 845 111) offers return flights from Heathrow - from £172 until the end of August.
Staying there
A double room at the Sofitel Marseille Vieux Port, 36 Boulevard Charles Livon, 13007 Marseilles (0033 4 91 15 59 00), costs from £102 a night.
Eating there
Chez Aldo, 28 rue Audemar Tibido, 13008 Marseilles (0033 4 91 73 31 55).
Drinking there
Brasserie New York, 33 quai des Belges (0033 4 91 33 91 79).


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Handbook of Clinical Psychology Competencies
pp 153-180
Translating Science into Clinical Practice
- Thomas L. SextonAffiliated withIndiana University
- , Christopher W. HanesAffiliated withIndiana University
- , Jeremy C. KinserAffiliated withIndiana University
In this chapter, we propose a developmental framework of competencies for the integration of science and practice. We believe a shortcoming of traditional competency models stems from the tendency to view science and practice as distinct entities that need to be linked rather than addressing their dialectical relationship. We argue that competencies for translating science into practice must acknowledge the inexorable link between the two. To accomplish this conceptual shift, we articulate the knowledge, attitudes, and skills necessary to define competencies pertinent to the realization of the scientist-practitioner. Four primary attitudes outlined include scientific mindedness, curiosity about how things work/what works, acceptance of ambiguity, and embracing the dialectical nature of science and practice. Core domains of knowledge identified include an understanding of scientific methods, familiarity with clinical intervention research, understanding the role of evidence based practice, and specification of clinical practices. We also propose skills necessary for the translation of science into practice. Skills include assessing scientific findings, consuming research through a levels of evidence lens, practicing research based clinical intervention protocols, and becoming a local scientist. We believe these three domains encompass both basic and expert competencies that are necessary for learning, developing, and functioning as a profession within the scientist-practitioner paradigm.
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- Title
- Translating Science into Clinical Practice
- Reference Work Title
- Handbook of Clinical Psychology Competencies
- Pages
- pp 153-180
- Copyright
- 2010
- 10.1007/978-0-387-09757-2_6
- Print ISBN
- 978-0-387-09756-5
- Online ISBN
- 978-0-387-09757-2
- Publisher
- Springer New York
- Copyright Holder
- Springer Science+Business Media LLC
- Additional Links
- Topics
- eBook Packages
- Editors
- Editor Affiliations
- 1. School of Professional Psychology, Pacific University
- 2. School of Professional Psychology, HCP/Pacific University
- Authors
- Thomas L. Sexton (1)
- Christopher W. Hanes (1)
- Jeremy C. Kinser (1)
- Author Affiliations
- 1. Indiana University, Bloomington, IN, USA
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Gosford Office & Showroom: (02) 4323 6322Wyong Office: (02) 4392 4222
Allcoast Locksmiths offers a range of Central Coast automotive locksmith services. This includes opening your vehicles, cutting car keys, replacement of ignition and door barrels, extracting broken or damaged keys and replacing lost keys.
With our onsite mobile units, we promptly come to you.
Central Coast Emergency Lockouts | Central Coast Domestic Locksmith | Central Coast Commercial Locksmith | Central Coast Automotive Locksmith | Central Coast Security Doors & Screens