astrocytes , the most abundant cell type of the brain , have been considered as the active players in the tripartite synapse with neurons . a wide variety of physiological functions of astrocytes have been identified ranging from structural and metabolic support to the modulation of synaptic transmission and information processing . they have also been found to play major roles in both the progression and repair of cns pathologies like inflammation , epilepsy , ischemia , neurodegenerative diseases , and neurodevelopmental disorders [ 13 ] . recently , it has been established that astrocytes actively influence neuronal plasticity and memory formation [ 49 ] . however , the reciprocal phenomenon involving astroglial plasticity in response to changes in neuronal activity has been less well explored and understood . indeed , it has been demonstrated that astrocytes display both short- and long - term plasticity similar to neurons [ 1022 ] . this review focuses on the ability of astrocytes to regulate extracellular levels of signalling molecules , particularly potassium ( k ) and glutamate , in a neuronal activity - dependent manner . the expression , properties , and regulations of the important cellular components will first be introduced . then , we will present and discuss important research findings demonstrating plastic modulations of these astroglial properties in response to changes in physiological neuronal activities . k and glutamate are essential and abundant neuroactive molecules participating in excitatory synaptic transmission of the brain . it has been reported that just a single action potential can elevate the resting level of extracellular k from 3 to 4  mm . this increase can also be stronger under conditions in which the extracellular space volume is decreased . during hyperactivity the excitatory neurotransmitter glutamate , on the other hand , is released via synaptic vesicles during excitatory synaptic activity and is not degraded extracellularly . its removal highly depends on diffusion and transporter systems . while intracellular concentration of glutamate is about 10  mm , extracellular glutamate level varies considerably from one compartment to the other . in fact , a study revealed that each glutamatergic synaptic vesicle contains around 4,000 molecules of glutamate . thus , it is not surprising that glutamate concentration in the synaptic cleft can increase transiently from < 20  nm to 1  mm following action potentials . on the contrary , extrasynaptic glutamate level has been reported to vary over a large range from 0.02 to 30  m [ 30 , 31 ] . although this variability is partly due to limitations in assessment techniques used , it can also be explained by different glutamate clearance rates and mechanisms between perisynaptic and nonsynaptic compartments . given that a significant accumulation of both k and glutamate occurs during physiological neuronal transmission , it is crucial that their levels be tightly regulated to prevent hyperexcitability and excitotoxicity . indeed , this important task is carried out predominantly and efficiently by neighboring astrocytes in the cns [ 26 , 27 ] . k clearance by astrocytes is conducted either by net k uptake or by k spatial buffering [ 26 , 33 ] . the first route largely involves the activity of cotransporters ( na - k - atpase or na - k-2cl ) , as well as k and cl channels . as a result , k ions transiently accumulate inside astrocytes and are released once extracellular k level drops . on the contrary , k spatial buffering allows uptake and redistribution of k from areas of high to low extracellular k concentrations , in which no significant net intracellular accumulation occurs . this later mechanism has been found to be more efficient than diffusion alone . in fact , it has been proposed that a single elongated astrocyte can effectively redistribute k from one end to the other . in mller cells of the retina , k siphoning , a specialized form of k spatial buffering in which glial k channel distribution directs k clearance into the vitreous humor , was extensively studied and found to involve inward rectifying k ( kir ) channels . in general , seven major subfamilies of kir channels have been identified ( kir1 to kir7 ) , each consisting of two transmembrane domains , an inner pore , and intracellular n- and c- termini . these channels are perfect candidates for regulation of k homeostasis as they have high open probability at glial resting membrane potentials and their conductance is variable relative to extracellular k concentrations . among the subfamilies , kir2 , kir4 , and kir5 are most commonly studied in glial cells of the brain . in particular , kir4.1 is highly abundant in astrocytes of different brain regions   and is enriched in astrocytic processes surrounding synapses and blood vessels . in mller cells , it was proposed that the strongly rectifying kir2.1 subtype is uniformally expressed at plasma membranes , enabling k influx from the synaptic plexiform layers , while the weakly rectifying kir4.1 subtype is responsible for the exit of k at the endfeet and lateral processes [ 4143 ] . this specific compartmentalization strongly reflects regional specific functions and regulations of kir channels . as glutamate is not degraded upon release , cellular mechanisms must exist to quickly remove excess glutamate in order to avoid receptor desensitization and excitotoxicity . it was shown in the neonatal hippocampus that glutamate clearance depends primarily on diffusion , whereas glial transporter uptake dominates in juvenile mice . this coincides with periods of synaptic maturation at which point extracellular volume significantly decreases rendering diffusion less effective . indeed , the glutamate transporter systems have been identified to be an efficient way of removing extracellular glutamate . the expression of excitatory amino - acid transporters ( eaats ) has been extensively studied revealing that eaat1/glast and eaat2/glt-1 are found mostly in glia while eaat3/eaac1 , eaat4 , and eaat5 are expressed in neurons . eaats can alternate between two conformations to transport glutamate inside the cells against its concentration gradients . this requires efficient cotransport of glutamate and ions ( three na and one h ) from the outside inwards and the counter - transport of one k ion from the inside to revert back to the outward conformation . crystal structures revealed that glutamate transporters are homomers containing three subunits [ 47 , 48 ] . this increases dramatically in the most active period of synaptogenesis ( during the third and fourth postnatal weeks ) and throughout adult life . in the adult hippocampus , astroglial glt-1 and glast are expressed at high amount and density ( 0.7 to 1.3  mm and up to 8,500 molecules per m ) . intriguingly , like kir channels , it was determined that the concentrations of glt-1 and glast on astroglial membrane vary considerably depending on neighboring structures . for example , membranes facing nerve terminals , axons , and dendritic spines have higher densities than those facing other astrocytes , cell bodies , or capillaries . to study these transporters , robust glutamate transporter currents have been successfully measured and characterized using electrophysiological techniques in hippocampal ca1 astrocytes [ 53 , 54 ] . furthermore , glt-1 and glast are believed to account for most of the glutamate uptake conducted by all eaats subtypes in mammalian cns , further suggesting the importance of glial glutamate removal . in terms of regional specific expression , glt-1 is mostly expressed in the forebrain and glast in the cerebellum , inner ear , circumventricular organs , and the retina . consequently , mice lacking glt-1 show lethal spontaneous seizures and are more susceptible to acute forebrain injury . on the other hand , those lacking glast have increased susceptibility to injury to the cerebellum and experience impaired motor coordination . apart from the expression of k channels and glutamate transporters , networks of astrocytes are also known to siphon extracellular molecules from areas of high to low concentrations via gap - junction channels . gap junction channels are formed across the membranes of two cells by two opposing hemichannels each composed of six cx subunits . they form channels allowing intracellular transfer of low molecular - weight molecules ( < 1.5  kda ) . thus , molecules like k and glutamate can be efficiently passed from cell to cell greatly facilitating extracellular clearance . gap - junctional coupling among astrocytes plays significant roles in both net k uptake   and k spatial buffering [ 60 , 61 ] , as well as glutamate clearance [ 62 , 63 ] . this mechanism offers an additional pathway for excess k ions and glutamate to be efficiently redistributed within networks of astrocytes . in various pathologies ; however , the propagation of neurotoxic substances away from the site of injury has been thought to be both protective and destructive [ 2 , 64 ] . interestingly , when astrocytic gap - junctional coupling was reduced by blocking cx43 , a decrease in glt-1 expression was also observed , suggesting possible regulatory roles of gap - junctional coupling in glial transporter activities . like many other ion channels , kir channels in the cns have been linked to many processes of the brain like ontogenesis , regulation of hormone secretion , neurotransmitter release , control of seizure activity , and regulation of cerebral blood flow . the properties regulating astroglial k clearance like channel activities and conductances are modulated by many factors . this includes changes in extracellular volume , ph , intracellular calcium ( ca ) and cl concentrations , and neurotransmitter release . in addition , the opening of kir channels is also sensitive to various types of extracellular and intracellular blockade . for examples , they are blocked by intracellular magnesium and polyamines as well as extracellular barium ( ba ) ions in a voltage - dependent manner . other studies have shown that they can also be activated by intracellular g - protein subunits   or adenosine triphosphate . interestingly , the water channel aquaporin 4 has been found to be strongly colocalized with kir4.1 channels in mller cells , possibly to prevent osmotic imbalance . they are also coregulated by the same dystrophin - associated protein complexes intracellularly for subcellular distribution and clustering . astroglial conditional knockout lacking kir4.1 induced in hippocampal astrocytes a severe depolarization   and in neurons enhanced responses to prolonged repetitive and to tetanic stimulations of schaffer collaterals ( scs ) . these mice were also found to have severe ataxia and stress - induced seizures and even die prematurely . the functional roles of glutamate transporters are diverse and vary among synapses . although glutamate transporters are expressed in different cell types in the cns , astrocytes are responsible for the majority of glutamate uptake and homeostasis . studies in the hippocampus have shown that while these transporters can affect the fast component of the synaptic glutamate transient via ampa and nmda receptors , they can also affect the slower components mediating spillover . in addition , both neuronal and glial transporters have been found to limit the glutamate spillover , reinforcing synapse independence . interestingly , synaptic plasticity could also be differentially influenced by the expression and activity of glial glutamate transporters . indeed , it was demonstrated that long - term potentiation ( ltp ) , but not long - term depression ( ltd ) , was impaired in the hippocampal ca1 region of glt-1 mutants . in the amygdala , inhibition of glutamate transporters resulted in a loss of input specificity of ltp important for fear conditioning . behavioral defects like anhedonia and impaired spatial memory have also been observed after blocking astroglial glt-1 activities . using glt-1 inducible knockout mice , a recent study has demonstrated that the resulting increase in synaptic excitability was responsible for pathological repetitive behaviours . there has been in vitro evidence indicating that coculturing astrocytes with neurons increases the expression of glt-1 and glast [ 78 , 79 ] . phosphorylation by protein kinase c ( pkc ) has been found to modulate the transport activity of glast , as well as cell - surface expression of glt-1 [ 81 , 82 ] . furthermore , glutamate transporters possess an sh - based redox regulatory mechanism   and may be regulated by serum- and glucocorticoid - inducible kinases . in addition , the cell - surface expression of glast in cultured astrocytes is rapidly upregulated by glutamate binding , suggesting modulations in transporter trafficking . interestingly , it was proposed that neuronal activity could modulate the distribution of glt-1 clusters in developing astrocytes . finally , processes like regulated glial endo-/exocytosis [ 8991 ] and surface diffusion   could also significantly account for differential surface expression of glial glutamate transporters . it is conceivable that expression levels , localization , and properties of glial channels and transporters largely determine the efficiency of k and glutamate clearance from extracellular space , thereby modulating synaptic plasticity . for this reason , relevant molecular components must be tightly regulated for optimal expression , distribution , and activities . over the years , dual electrophysiological recordings in acute hippocampal slices have allowed the identification and pharmacological dissection of synaptically - evoked astroglial currents while monitoring neuronal plasticity [ 4 , 21 , 93 ] . a complex astroglial biphasic response evoked by single stimulation of scs ( 0.05  hz ) from stratum radiatum hippocampal astrocytes has been identified and it consisted of a fast outward current , reflecting the extracellular field potential generated by receptors on ca1 pyramidal neurons , followed by a slow inward current persisting for several seconds ( figure 1 ) . this long - lasting k current mediated by kir4.1 channels constitutes ~80% of the total astrocytic currents and can be isolated in the hippocampus by addition of kynurenic acid ( figure 1(c ) , ik ) , an ionotropic glutamate receptor antagonist , which has no direct effect on hippocampal passive astrocytes connected by gap junctions and lacking glutamate ionotropic receptors . in addition , a transient glutamate transporter current ( iglut ) can then be isolated by subsequent addition of glutamate transporter antagonists dl - threo--benzyloxyaspartic acid ( tboa ) and dihydrokainate ( dhk ) [ 6 , 21 , 53 , 9396 ] . finally , a slow residual current ( ires ) mediated by gaba transporters ( gats ) and kir4.1-independent k channels remains . interestingly , such astrocytic currents increased with neuronal input over a wide range of fiber volley amplitudes , suggesting that glial cells are reliable sensors of glutamate release that occurs during both moderate and strong neuronal activities [ 21 , 53 , 96 ] . evidently , one of the many roles of astrocytes in the cns is to take up excess neuroactive substances resulting from physiological neuronal transmission . such processes are undoubtedly subject to stringent regulations and are elegantly compartmentalized in the brain . while they have been found to take part in the shaping of neuronal activities , the proposition that these processes are also plastic and may be neuronal activity - dependent is just becoming of interest . in the following sections , we focus on important research findings supporting this notion , while proposing possible molecular mechanisms that might be involved in making these types of astroglial plasticity possible . in order to maintain proper brain homeostasis , the process of astroglial k clearance must also adapt to handle dramatic changes in extracellular k levels over different strengths of synaptic activity . using electrophysiological techniques , there have only been a few studies demonstrating short- or long - term activity - dependent plastic changes in astroglial k uptake . nevertheless , they uncover unique characteristics of astrocytic currents , which are of important value in the field . thus , we summarize these research findings concentrating on the similarities and differences between astroglial and neuronal functional plasticity . we will also present novel findings to further illustrate the involvement of activity - dependent k clearance by hippocampal astrocytes during mild activities . hippocampal ca3-ca1 synapses exhibit several forms of short - term plasticity induced by distinct stimulation protocols of scs , which are mediated by changes in presynaptic glutamate release probability ( pr ) [ 21 , 53 , 96 ] . as we have previously reported , synaptically evoked astroglial currents in the hippocampus exhibit complex characteristics [ 21 , 93 , 97 ] . in particular , upon dissection of astrocytic current components , a long lasting kir4.1 channel - mediated current ( ik ) and a residual current component ( ires ) could be identified . a classical type of short - term plasticity is paired - pulse facilitation ( ppf ) , which is assessed by two successive stimulations with a short interstimulus interval ( isi ) of 40  ms . an increase in the magnitude of the second postsynaptic response is thought to result from the residual increase of ca concentration in presynaptic terminals in response to the first stimulation . a common practice in electrophysiological measurements of neuronal - related response is to quantify the peak ( or slope ) of the response measured from the baseline immediately before the stimulation as illustrated in figure 2(a ) as the  astroglial facilitation  method . with this , it is evident that following paired - pulse stimulation at different frequencies ( 0.5 to 50  hz ) , while neuronal field excitatory postsynaptic potentials ( fepsps ) potentiated more at an isi of 40  ms , astrocytes exhibited a robust potentiation of ik , which was strongest at 20  ms isi instead ( figures 2(b ) and 2(c ) ) . similarly , ires also potentiated but to a much lesser extent , similar to the level of fepsps . in addition to ppf , prolonged repetitive stimulation ( 10  hz for 30  s ) and tetanic stimulation ( 100  hz for 1  s ) of scs are two other well - known stimulation protocols used to induce short - term plasticity . repetitive stimulation induces fast and transient potentiation of neuronal fepsps , as a result of the massive release of glutamate , followed by rapid response depression , due to the depletion in glutamate vesicular pools ( figures 2(d ) and 2(e ) ) . the tetanic stimulation , on the other hand , is commonly used to induce posttetanic potentiation ( ptp ) , a transient potentiation lasting a few minutes ( figures 2(f ) and 2(g ) ) . when astrocytic currents are quantified using the  astroglial facilitation method , a rapid depression of both ik and ires was detected during the repetitive stimulation ( figure 2(e ) ) . this was unexpected given the strong facilitation of these currents upon paired - pulse stimulation . surprisingly , during the tetanus , both ik and ires initially potentiated much more strongly than during repetitive stimulation . this was followed by depression with ires much more slowly than ik ( figure 2(g ) ) . moreover , compared to the neuronal response , ik and ires only showed mild ptp immediately after the tetanus . it is important to note that , due to the longer - lasting nature of astrocytic ik and ires current responses compared to neuronal fepsps , an incomplete recovery of the baseline before subsequent stimulations is often observed . thus , such significant baseline shift must be taken into account during the quantification . to fully acknowledge this factor , it is therefore more appropriate to measure evoked current amplitude of each response from the initial baseline immediately before the first stimulation as illustrated in figure 2(h ) . indeed , this alternative method we define as  astrocytic summation  revealed very different and sometimes completely opposite short - term plastic behaviour upon repetitive and tetanic stimulations . during repetitive stimulation , both astrocytic ik and ires show short - term summation but with different kinetics to neuronal fepsps . specifically , they initially summate up to ~400% ( compared to ~150% potentiation in fepsps ; figure 2(e ) ) , which lasted for 20  s and decreased back to baseline during the last 10  s of the stimulation ( figure 2(j ) ) . this slower kinetics could be explained by k release from both pre- and postsynaptic elements leading to a uniform bulk increase of extracellular k level over larger zones requiring more time to be removed . such behavior has been previously reported in other brain regions and is thought to correspond to glial depolarization leading to extracellular k build - up over time , as originally described in the optic nerve   and subsequently in the cortex in vivo [ 98100 ] . interestingly , during a tetanic stimulation , greater distinctions between neuronal fepsps and astroglial currents were uncovered using this quantification method . while fepsps mildly potentiated during the initial phase of the tetanus ( ~150% ; figure 2(g ) ) , astroglial ik showed a stronger and longer - lasting summation ( reaching ~400% ) , which continued during the course of the stimulation ( figure 2(k ) ) . remarkably , the ires exhibited an even stronger summation ( ~1000% ; figure 2(k ) ) during the tetanus . moreover , ptp observed in neuronal fepsps was not detected in either ik or ires . in contrast , a posttetanic depression of current undershoot of mild ( ~30% ) and stronger ( ~200% ) magnitudes were detected in ik and ires , respectively ( figure 2(k ) ) . similar undershoot response has been characterized following high - frequency stimulations   and could represent a period of redistribution of k in the extracellular space to avoid overdepletion . in addition , the astroglial facilitation quantification appeared to underestimate the undershoot currents rendering ik and ires mildly potentiating after tetanic stimulation . it is important to point out that ppf , quantified by comparing only two successive stimulations at a time , does not seem to differ significantly using the two methods ( figures 2(c ) and 2(i ) ) . with this , we stress the importance of using an appropriate quantification method , astrocytic summation ,  when measuring astrocytic slow currents , which takes into account baseline shifts over successive high - frequency stimulations . when comparing short - term plasticity of astrocytic currents and neuronal response , it is also important to consider their differential characteristics towards lower stimulation frequencies . for this reason , and given that ~80% of astroglial slow inward current ( itot ) is composed of ik , we measured astrocytic inward current itot in response to trains of scs stimulation at a range of lower frequencies ( 0.75 , 1.5 , 3 , and 10  hz for 30  s ) in hippocampal slices . importantly , this was performed simultaneously with neuronal excitatory neurotransmission recordings in order to correctly assess both neuronal and astroglial ( figures 3(a ) , 3(c ) , 3(e ) , and 3(g ) ) short - term plastic behavior . as illustrated in figure 3 , neurotransmission exhibited weak short - term plasticity following 0.753  hz stimuli for 30  s ( with potentiation up to 120 and 150% at 1.5 and 3  hz , resp . ) . astroglial itot , on the other hand , remarkably showed very strong summation of ~400% during 0.75  hz stimulation ( figure 3(b ) ) . such summation was enhanced to ~500% during 1.5  hz and even ~600% during 3  hz stimulations ( figures 3(d ) and 3(f ) ) . in response to 10  hz repetitive stimulations , a near 800% summation of astroglial itot was observed as previously reported ( figure 3(h ) ) . in addition , such short - term summation exhibited longer - lasting kinetics than the corresponding neuronal response , which could be explained by the dominating ik component in itot , which is strongly influenced by the rate of k clearance from the extracellular space . altogether , these data indicate that astroglial slow inward current short - term plasticity is also strongly involved at low frequencies of repetitive stimulations . more importantly , this frequency range is below what is usually used for neuronal short - term plasticity studies and induced only weak potentiation in neuronal fepsps . it can be postulated that short - term plasticity of astroglial k uptake observed at low frequencies may be a mechanism of activity - dependent upregulation of k buffering important for controlling neuronal responses . while ltp and ltd have been well established and described in neurons to be associated with learning and memory , the topic of astroglial long - term plasticity is yet to be characterised . indeed , most of the existing studies concerning astroglial long - term plastic properties have concentrated on glutamate receptors [ 11 , 15 ] and transporters [ 12 , 16 , 19 , 20 , 54 , 96 ] ( see section 6 ) , leaving k current - mediated plasticity virtually unexplored . nevertheless , there have been two important reports on changes in evoked astrocytic currents or potentials upon long - term synaptic potentiation . the first study by ge and duan   was carried out in the hippocampus ca1 region . using electrophysiological techniques , the authors showed that tetanic stimulation ( 100  hz for 1  s ) of scs evoked persistent ltp in fepsps of ca1 pyramidal neurons . this was accompanied by a ltp - like response in astroglial slow inward current resulting from membrane depolarization . interestingly , similar to short - term plasticity of astroglial inward current described above , the astrocytic response exhibited stronger potentiation than the neuronal fepsps during both the initial and late phases of ltp . furthermore , this astroglial ltp was sensitive to blockers of nmda receptors and k channels , but not intracellular ca level in astrocytes . this suggested a mechanism involving postsynaptic nmda receptor activation leading to accumulation of extracellular k. such increase in extracellular k level was estimated to be from 5.1 to 17.9% corresponding to an increase in astrocytic depolarization from 1 to 3  mv following ltp induction . the authors , however , postulated that the actual depolarization at peripheral astrocytic processes is likely to be even higher compared to the soma . finally , it is important to note that although ltp of astroglial depolarization in this case may be a passive response , the resulting downstream astroglial responses may serve as persistent feedback signals in turn modulating neuronal behavior . although not directly tested in this study , it is likely that such plasticity is largely mediated by astrocytic kir4.1 channels as we have demonstrated that synaptically evoked astrocytic currents consisted of ~80% kir4.1 channel dependent ik current . however , whether this long - term increase in k current is mediated by channel expression , localization or other factors remains unanswered . it is also possible that an accompanying decrease in glial glutamate uptake resulting from membrane depolarization plays a role in the progression of the astroglial ltp observed . building upon these findings , a later study reported by zhang and colleagues   also described an ltp - like response in astrocytes , induced by strong high - frequency stimulation ( hfs ; 8 trains of 8 pulses at 200  hz with intertrain interval of 2  s ) of the perforant path in the dentate gyrus ( dg ) of the hippocampus . indeed , a ~400% potentiation in astroglial membrane depolarization induced by hfs , referred to as excitatory postsynaptic astrocytic potentials ( epaps ) by the authors , was observed and lasted for more than 30  min . importantly , the magnitude of this astroglial potentiation was more pronounced than that during neuronal ltp upon the same hfs stimuli . next , it was demonstrated that neither glutamate transporters ( glt-1 and glast ) nor metabotropic glutamate receptors ( group i mglurs ) were responsible for the astroglial epaps potentiation , as ltp induction was unaffected by treatments with dhk ( glt-1 inhibitor ) , threo--hydroxyaspartic acid ( tha ; a glast inhibitor ) , or dihydroxyphenylglycine ( dhpg ; a group i mglur agonist ) . however , by combining astrocytic epaps recordings with single - cell reverse transcription - polymerase chain reaction ( rt - pcr ) , the authors elegantly showed that ltp induction required functional nmda receptor activation in astrocytes at the granule cell body layer of the dg . indeed , significant pcr products for nmdar subunits ( nr1 , nr2a , and nr2b ) were also detected , in agreement with previously characterised functional astroglial nmda receptors on astrocytes . altogether , even though this study did not directly investigate astroglial k currents , it is likely that , similar to the first study , the nmda receptor - mediated astroglial ltp observed here is also associated with changes in extracellular k increase . in summary , although astrocytes are sensitive to and respond quickly to changes in extracellular k levels , not much is known about how this response is regulated in a neuronal activity - dependent manner in terms of both short - term and especially long - term plasticity . nevertheless , these few available studies provided encouraging first evidence of the existence of such form of plasticity , as well as how they can be appropriately characterised . with this , it is important to focus future research on detailing the underlying mechanisms in terms of identifying channel subtypes and regulating factors involved , as well as the interconnection with other types of astroglial plasticity like glutamate uptake . while one of the main functions of astrocytes is to remove excess glutamate during excitatory neurotransmission , it is of interest to know if astroglial glutamate clearance also exhibits different forms of short- and long - term plasticity in order to adapt to changing neuronal activities . in particular , several studies have focused on electrophysiological measurements of astroglial synaptically - activated glutamate transporter currents ( stcs ) as a means of determining glial glutamate transporter activities . remarkably , both short- and long - term plasticity have been documented either in synchrony with or opposite to changes in synaptic transmission . here , we review these studies focusing on the plasticity of astroglial stcs and discuss their roles in various experimental models and brain areas . similar to the studies of astroglial ik discussed above , electrophysiological measurements using the same stimulation protocols with ppf protocols , it was observed by diamond and colleagues   that astroglial stcs remarkably displayed a 1.9-fold ppf ( isi = 50  ms ) similar to the 1.4-fold ppf of ampa receptor - mediated epscs in ca1 pyramidal neurons ( figure 4(a ) ) . this supported the notion that glial transporter currents accurately monitored glutamate release at ca3-ca1 synapses [ 12 , 21 , 53 , 93 , 94 , 96 ] . paired - pulse ratio ( ppr ) of glial stcs , in contrast to ampa - epscs , was however not directly connected to the pr , as manipulation of pr by either changing extracellular ca concentration or blocking adenosine a1 receptors did not induce any change in glial ppf . in the cerebellum , bergmann cells are specialized glial cells , which interestingly express both glutamate transporters and glua2-lacking ampa receptors that are permeable to ca [ 105 , 106 ] . with this in mind , the authors measured a striking 4.2-fold ppf of extrasynaptic currents ( escs ) induced by parallel fibers paired stimulations , whereas a similar protocol applied to purkinje neurons only induced a 2-fold increase . upon isolation of glutamate uptake components from the escs , ppf has also been detected in both medium - sized spiny neurons , sensors of cortical activity , and glial stcs following stimulation of layer 5 of the somatosensory cerebral cortex . interestingly , for isis of 4 to 10  ms , while cortical stcs still displayed ppf , epscs exhibited depression . the authors postulated that these opposite observations could be due to a facilitation of glial glutamate uptake leading to decreased glutamatergic postsynaptic activation . apart from ppf , glial response to repetitive stimulation ( 10  hz for 30  s ) was also investigated . with such stimulation protocol , it was demonstrated that astroglial stcs , in synchrony with neuronal responses , first potentiated and then depressed with a similar time course to that of fepsps in the hippocampus . in the cerebellum , repetitive stimulation of parallel fibers even at low frequencies ( 0.1 to 1  hz ) displayed initial glial escs facilitation similar to scs stimulation followed by depression , suggesting that distant bergmann glial processes are in a more depolarized state than the soma ( figure 4(b ) ) . finally , similar to fepsps generated by neurons , astroglial stcs also initially potentiated and then depressed in response to 100  hz tetanus stimulation for 1  s [ 10 , 21 ] . furthermore , a train of 10 pulses at 100  hz stimulation of cerebellum parallel fibers generated facilitation of glial escs amplitude that gradually decreases and subsequently turned to depression ( figure 4(c ) ) . taken together , these studies indicate that hippocampal , cortical , and cerebellar astroglial stcs displayed a neuronal - like plasticity and monitored short - term excitatory synaptic transmission by reflecting activities of surrounding synapses . as astroglial stcs exhibit various short - term plastic changes induced by modifications of neurotransmitter pr , it is also of interest to investigate whether such plasticity can also be long - lasting . indeed , using paired granule cell - glial cell recordings in cerebellar cultures , ltp of ca - permeable ampa receptor glial currents has been induced by prolonged 4  hz stimulation of the granule cell [ 15 , 16 ] . this provided one of the first evidence showing that astroglial glutamate transporter currents , in addition to neuronal transporters , are able to display ltp . ltp of glial transporter currents could be induced in the presence of postsynaptic ca chelation and glutamate receptor antagonists but was blocked by removal of external ca during the tetanus , suggesting that a part of the cerebellar ltp is expressed presynaptically through modifications of glutamate pr . over the years , many insights regarding astroglial glutamate uptake have been obtained from neuronal stcs displaying long - term plasticity . an important study on neuronal glutamate transporters ( eaat4 ) in cerebellar purkinje cells has shown that stcs undergo ltp in response to brief tetanic stimulation of climbing fibers . importantly , the increase in neuronal glutamate transporter current was coupled to ltd of ampa - epscs , suggesting the involvement of an integrated mechanism that protects purkinje cells from glutamate excitotoxicity . other studies have shown that neuronal and astroglial glutamate transporters have distinct roles during long - term changes in neuronal activities . in the hippocampal ca1 area , it was observed that eaac1 , the predominant neuronal glutamate transporter , is upregulated during the early phase of ltp ( e - ltp ) and fear conditioning in vivo . the enhanced glutamate uptake accompanying the increased surface expression of glutamate transporters was the likely mechanism limiting glutamate spillover during e - ltp . as neuronal eaac1 and glial glt-1 together account for more than 80% of glutamate uptake in the hippocampus , the changes in glt-1 expression and activity was also investigated in this study . to assess differential contributions of these two transporters , the authors showed that the increase in glutamate uptake during e - ltp , observed together with an increase in eaac1 expression , did not require macromolecular synthesis , and was not sensitive to dhk , a selective inhibitor of glt-1 . this increase in glutamate uptake that occurred at the postsynaptic element could prevent postsynaptic glutamate receptor desensitization during strong neuronal activity or limit glutamate spillover . although glial glt-1 activity was not altered during e - ltp , a later study revealed an increase in glial glutamate uptake during the late phase of ltp ( l - ltp ) , which could be explained by an upregulation of glt-1 expression at the membrane resulting in increased astroglial glutamate uptake ( figures 4(d ) and 4(e ) ) . this was found to be sensitive to protein synthesis and transcription inhibition , as well as dhk , and may participate in controlling both presynaptic release and extracellular diffusion of glutamate . additionally , the same group later demonstrated that an increase in glt-1 activity above basal level , and the accompanying enhancement in glutamate uptake , appears to be responsible for the induction of additional ltp ( figure 4(f ) ) . this interesting discovery demonstrated the importance of long - term upregulation of astroglial glutamate uptake in the maintenance of synaptic plasticity . these studies together supported differential regulations of both neuronal and glial glutamate transporters during the progression of ltp . finally , bergmann glia ampa receptors and glutamate transporters have been found to display activity - dependent ltd during parallel fibers stimulation . bellamy and ogden   revealed that this plasticity of cerebellar glial cells was , however , not observed in synchrony with surrounding neuronal activity . indeed , ltd of glial escs and ca - permeable ampa receptor currents was induced in bergmann glia using a 0.2  hz frequency stimulation that does not generate any change in evoked excitatory postsynaptic current ( epsc ) amplitude from purkinje neurons . taken together , these results revealed that astrocytes are sensitive to different forms of plasticity . long - term plasticity of both neuronal and astroglial stcs are essential regulators of neuronal homeostasis . therefore , by controlling presynaptic neurotransmitter release , as well as extracellular diffusion of glutamate to prevent postsynaptic receptors desensitization , these long - term mechanisms are necessary to protect the tripartite synapse against glutamate excitotoxicity that occurs during sustained neuronal activity ( e.g. , neurological disorders such as epilepsy , addiction , and neurodegenerative diseases [ 113 , 114 ] ) . while it is evident that astrocytes display both short- and long - term plasticity in glutamate uptake , a description of the possible molecular mechanisms underlying such activity - dependent regulation remains unexplored and still needs to be clarified . interestingly , and due to its simple nervous system organization , the marine mollusk aplysia californica has been used as a useful model to study changes in neural circuitry that occurred during specific behaviour like long - term sensitization ( lts ) [ 115 , 116 ] . similar to later discoveries in the ca1 region , enhanced glutamate uptake was triggered by in vivo treatment with serotonin or electrical stimulation , which are responsible for the induction of lts in aplysia . importantly , the pka , map , and tyrosine kinase pathways appeared to regulate glutamate uptake by either transcription of the glutamate transporter or posttranslational modifications such as phosphorylation [ 82 , 117 , 118 ] . in addition , the primary high affinity glutamate transporter in aplysia , apgt1 , is transported through the endoplasmic reticulum - trans - golgi network vesicular trafficking system from the sensory neuron somata to the terminals . this pathway may be the mechanism underlying the increase in apgt1 at the membrane , and consequently leading to glutamate uptake observed during long - term plasticity [ 119 , 120 ] . taking advantage of the similarities in learning and memory behaviour between aplysia and higher vertebrates , these proposed pathways give important insights into the molecular mechanisms governing plasticity of glutamate uptake in glial cells . in fact , the importance of glial glutamate transporter trafficking has already been under consideration . by using a combination of high - resolution live imaging and electrophysiological recordings both in vitro and in vivo , a recent study   provided additional evidence regarding the role of astrocytic glt-1 surface trafficking in shaping excitatory synaptic transmission . noteworthy , the diffusion coefficient of glt-1 was one of the highest reported while the fraction of immobile transporters was one of the lowest . these findings , together with an earlier study , clearly suggest that scaffolding and/or anchoring proteins may directly control transporter surface diffusion . additional studies focused on the identification of both neuronal and glial glutamate transporter binding partners will further clarify how short- and long - term changes in glutamate transporter could occur during neuronal activity . apart from short- and long - term plasticity of glutamate uptake , astrocytes also display changes in their morphology in response to sensory stimuli or neuronal activity [ 14 , 17 , 123 , 124 ] . indeed , it has recently been reported that ltp transiently increases the motility of hippocampal perisynaptic astrocyte processes , which is mediated by calcium signalling induced by activation of metabotropic receptors . in addition , structural plasticity of astroglial processes has also been observed in the somatosensory cortex following whisker stimulation [ 123 , 124 ] . remarkably , such morphological plasticity has been described to modify glutamate transporter activities in several brain areas . oliet and colleagues   have observed that glutamate level in the synaptic cleft was higher in lactating animals than virgin or postlactating animals and correlated it to a reduced astrocytic coverage onto supraoptic nucleus ( son ) neurons . in addition , inhibition of son glutamate uptake by dhk consequently resulted in glutamate spillover , which activated presynaptic group iii mglurs leading to a lower glutamate pr . few years later , using single whisker stimulation paradigm , which increases sensory activity , another group showed an increase in glt-1 and glast protein expression in barrels corresponding to the stimulated whisker . notably , morphometric analyses using serial electron microscopy confirmed an increase in astroglial coverage to the bouton - spine interface , suggesting that plasticity of glutamate transporters in the somatosensory cortex may prevent glutamate spillover to surrounding areas . finally , we have shown that hippocampal astrocytes display cx30-mediated morphological changes , which in turn regulates astroglial glutamate uptake . an increase in the insertion of astroglial processes into synaptic clefts was observed in cx30 deficient mice . such increased invasion of excitatory synapses could facilitate glutamate uptake observed in these mice . together , these important studies concurrently demonstrated enhanced synaptic coverage by astrocytic processes with increased glutamate uptake via astroglial glutamate transporters in different brain regions . this implies that astrocytes may take advantage of the positioning of their dynamic processes to regulate glutamate removal from the synaptic cleft . astrocytes not only sense but also respond to neuronal activities and have been recognized as active players at the tripartite synapse . over the years , it has been of immense interest for researchers to explore such intricate relationships between neurons and astrocytes . in particular , among many astroglial functions , their abilities to remove excess k and glutamate upon neuronal activity are thought to be essential mechanisms important for the maintenance of extracellular homeostasis and thus allow proper functioning of the brain . for this very purpose , astrocytes express functional k channels as well as glutamate transporters . with the help of their elaborate gap - junctional networks , they have been found to efficiently take up and redistribute excess neuroactive substances throughout the brain . interestingly , over recent years , the focus has extended to activity - dependent plasticity of these properties . it was hypothesized that in response to changes in synaptic strengths , these astroglial properties can be modulated in an activity - dependent manner , similar to neuronal synaptic plasticity . indeed , both short- and long - term plasticity of such nature have been documented as presented in this review . it is important to note that in some cases , astroglial responses behave in concert with neurons [ 10 , 12 , 21 ] . however , in other cases , they exhibit unique kinetics   and differential regulations [ 19 , 20 ] as compared to their neuronal counterparts . importantly , we have also shown here that astrocytic inward currents display robust summation during mild - stimulations , suggesting differential sensitivity to the surroundings by neurons and astrocytes . with these emerging findings , we show in this review that astroglial properties indeed display different forms of plasticity in response to changing neuronal activities . nevertheless , it has been postulated that channel and transporter expression , clustering , and trafficking might play important roles [ 19 , 92 , 122 ] . moreover , astrocytes may also undergo morphological changes in synaptic coverage by their fine processes , thereby modulating uptake [ 14 , 17 , 18 ] . in order to better understand activity - dependent astroglial plasticity and how it may be triggered and regulated , it is essential to explore the underlying cellular and molecular mechanisms governing these changes . it is with this knowledge of plasticity from both neuronal and glial points of view , and how they are interconnected , that we can fully appreciate the dynamic aspects of brain processes like learning and memory .
recent evidence has shown that astrocytes play essential roles in synaptic transmission and plasticity . 
 nevertheless , how neuronal activity alters astroglial functional properties and whether such properties also display specific forms of plasticity still remain elusive . here , we review research findings supporting this aspect of astrocytes , focusing on their roles in the clearance of extracellular potassium and glutamate , two neuroactive substances promptly released during excitatory synaptic transmission . their subsequent removal , which is primarily carried out by glial potassium channels and glutamate transporters , is essential for proper functioning of the brain . 
 similar to neurons , different forms of short- and long - term plasticity in astroglial uptake have been reported . 
 in addition , we also present novel findings showing robust potentiation of astrocytic inward currents in response to repetitive stimulations at mild frequencies , as low as 0.75  hz , in acute hippocampal slices . 
 interestingly , neurotransmission was hardly affected at this frequency range , suggesting that astrocytes may be more sensitive to low frequency stimulation and may exhibit stronger plasticity than neurons to prevent hyperexcitability . 
 taken together , these important findings strongly indicate that astrocytes display both short- and long - term plasticity in their clearance of excess neuroactive substances from the extracellular space , thereby regulating neuronal activity and brain homeostasis .