the brain has the amazing ability to adapt through its capability to change in response to experience and use . this fundamental property of plasticity serves to learn and remember complex tasks , obtain rewards , or even recover after injury . surprisingly , with constant dynamic changes occurring in the brain , neuronal activity remains stable over an entire lifespan . our brains appear to be constructed in such a manner that the mechanisms involved in learning and memory can be balanced by another distinct form of neuronal modulation , homeostatic plasticity . these two forms of plasticity coexist to adapt to the changing sensory world while maintaining a balance of neural activity within a physiological range . hebbian synaptic plasticity is associative and input specific , which strengthens or weakens the transmission efficacy of individual synapses . long - term potentiation ( ltp ) and depression ( ltd ) , the two best studied forms of hebbian plasticity , are widely considered to be the cellular mechanisms for learning and memory . however , given the positive - feedback nature of hebbian plasticity , this form of synaptic modulation could potentially result in synapses of either functional saturation or silence , driving the whole network into an unstable state if left unchecked . hebbian synaptic plasticity therefore necessitates distinct homeostatic mechanisms that can stabilize a network in the face of constant dynamic changes in synaptic strength . indeed , neuronal networks use an array of homeostatic negative - feedback mechanisms that allow neurons to assess their activity and adjust accordingly so as to restrain their activity within a physiological range [ 13 ] . at the neuronal level , homeostatic plasticity aims to maintain a stable firing rate of action potentials . this can be achieved through adjustments in the strength of synaptic inputs , neuronal excitability , neuronal connectivity , or the balance between excitation and inhibition . among these possibilities , regulation of synaptic strength has been the most extensively studied and is believed to be the most crucial measure in homeostatic regulation . this form of regulation , known as homeostatic synaptic plasticity or synaptic scaling [ 4 , 5 ] , is expressed mainly by an alteration in ampar synaptic accumulation [ 1 , 69 ] . during homeostatic regulation , ampar numbers at the postsynaptic surface are accordingly scaled up- or downwardly in response to activity deprivation or overexcitation , respectively , presumably via changing ampar trafficking processes including receptor insertion and internalization ( figures 1 and 2 ) . in central neurons , the most studied model of homeostatic synaptic plasticity is activity deprivation by a sodium channel blocker , tetrodotoxin ( ttx ) . when cultured cortical neurons are incubated with ttx to chronically abolish action potentials and thus silence network activity , the synapse responds in a compensatory manner , resulting in an increase in the strength of synaptic transmission [ 4 , 10 , 11 ] . by measuring ampar - mediated miniature excitatory postsynaptic currents ( mepscs ) , it has been shown that chronic suppression of network activity results in an upscaling of synaptic activity [ 4 , 12 , 13 ] . conversely , chronic network hyperactivation , commonly induced by bath application of bicuculline , an antagonist of the inhibitory gamma - aminobutyric acid a ( gabaa ) receptors , results in a homeostatic downscaling in mepscs . homeostatic plasticity has traditionally been considered a response that globally affects the entire synapse population of a neural network or a whole neuron , in which ampar accumulation at every synapse is up- or downwardly scaled according to activity manipulation [ 6 , 14 ] . in practice , global homeostatic regulation is usually induced by bath application of reagents that affect the activity of the whole network , in which mepsc amplitude and ampar synaptic amounts at each cell in the network are affected in a compensatory manner . in addition to a network scale , global homeostatic regulation has also been studied at a level of individual neurons . by overexpression of inward - rectifier potassium channels , show that inhibition of single neuron activity by local perfusion of ttx at the somatic area induces homeostatic regulation in mepsc and ampar synaptic expression . in a recent study , individual neurons expressing light - sensitive channels are selectively activated for 24  hrs . using this paradigm , goold and nicoll demonstrate that chronic activation of single neurons lead to a homeostatic reduction in ampar - mediated synaptic transmission . in contrast to global regulation , recent studies indicate that homeostatic synaptic responses could also occur locally at subcellular regions [ 8 , 14 , 17 , 18 ] . in cultured hippocampal neurons , synapses in a small region of dendrites are suppressed by microperfusion of ttx together with the n - methyl - d - aspartate ( nmda ) receptor antagonist , apv . using this method , sutton et al . however , in another study , local application of ttx on dendrites fails to alter synaptic ampar expression . this discrepancy may be due to the difference between activity manipulation paradigms ( with or without nmda receptor inhibition ) . although findings indicate that the traditionally considered global homeostatic plasticity can be induced at local dendritic areas , whether it occurs at the level of individual synapses , an important question regarding synapse functional stability , has not been studied until recently . our work shows for the first time that the homeostatic response is indeed employed locally at the single synapse level [ 18 , 20 ] . in cultured hippocampal neurons , overexpression of kir2.1 inward - rectifier potassium channels to selectively inhibit the activity of individual presynaptic terminals results in a homeostatic increase in corresponding postsynaptic ampar expression . to study the opposite paradigm , hou et al . selectively activate single synapses by employing a light - gated glutamate receptor [ 18 , 21 ] . we demonstrate that the level of ampars at excited synapses is selectively downregulated via receptor internalization and proteasomal degradation . although ampar trafficking is likely shared by global and single synaptic homeostatic responses , it remains unclear whether similar or distinct signaling cascades and molecular components are adopted in global versus single - synaptic homeostatic regulation . recent studies have shown that different functional molecules and signaling cascades are involved in the expression of homeostatic up- or downregulation of synaptic activity and ampar expression . for instance , tnf , the pi3k - akt pathway , integrin , glua2-lacking ampars ( cp - ampars ) , and retinoic acid have been implicated in inactivity - induced homeostatic upscaling , whereas pick1 , a postsynaptic scaffolding protein , is involved in overexcitation - induced downscaling . other molecules , such as camks , arc / arg3.1 , and certain cell adhesion molecules , have been implicated in both directions of homeostatic regulation . given that ampars are the substrate for the expression of homeostatic plasticity , it is not surprising that most of these molecules and cascades are known to play an important role in ampar trafficking and synaptic accumulation . this paper summarizes recent findings on the signaling molecules and cascades that regulate ampar trafficking in homeostatic plasticity ( figure 3 ) . tumor necrosis factor - alpha ( tnf ) is an inflammatory cytokine that is involved in inflammation , immune activation , cell death , and degradation [ 22 , 23 ] . in addition to its important functions in immune responses , tnf is also important in maintaining the neural network stability [ 24 , 25 ] . tnf has been found to mediate the global homeostatic upscaling of mepscs and postsynaptic ampars induced by prolonged ttx treatment . when incubated with medium obtained from ttx - treated neural cell cultures , cultured hippocampal neurons globally scale up mepsc amplitudes and postsynaptic ampar numbers . this effect can be abolished by applying exogenous high - affinity tnf receptors to scavenge tnf from the medium , indicating a critical role of free tnf released to the extracellular environment to mediate synaptic upscaling during activity deprivation . to further support tnf signaling in homeostatic plasticity , ttx - induced global upscaling in mepsc interestingly , this abolished scaling can be rescued by coculture of tnf knockout neurons with wild - type glial cells . however , although neurons produce tnf by themselves , coculture of wild - type neurons with tnf knockout glial cells still abolishes the upscaling in wild - type neurons . therefore , tnf released from glia , but not neurons , plays a crucial role in the induction of global , slow homeostatic synaptic upregulation . tnf seems to mediate ttx - induced synaptic upscaling by regulating the trafficking and synaptic accumulation of ampars . studies have shown that application of tnf in cultured hippocampal neurons induces a rapid translocation of ampars ( within 15  min ) to the postsynaptic domain in a subunit - specific manner [ 26 , 27 ] . after tnf treatment , the delivery of ampars to postsynaptic surface is enhanced significantly , through downstream activation of pi3k pathway . it also has been found that the effects of tnf on ampar trafficking are mainly through tnfr1 but not tnfr2 . of note , the enhanced delivery of glua1 subunit occurs faster than glua2 , leading to the generation of glua2-lacking ampars . calcium influx through these special type of ampars is believed to have an important role in the initiation of homeostatic response   ( see section 4.6 on cp - ampars ) . in addition to enhancing ampar synaptic delivery , tnf also decreases the trafficking of gabaa receptors to the synapses . thus , tnf-mediated synaptic homeostatic regulation of neuronal activity could be achieved via rebalancing excitation and inhibition . calcium ( ca ) is one of the most important signaling molecules in the nervous system . in neurons , ca transients from ligand- and voltage - gated calcium channels and intracellular calcium stores activate a family of ser / thr protein kinases known as ca / calmodulin - dependent protein kinases ( camks ) to execute signaling functions [ 31 , 32 ] . among all camks , camkii and camkiv are mostly known to be closely involved in synaptic transmission and different forms of synaptic plasticity by regulating receptor synthesis and trafficking [ 32 , 33 ] , through their ability to either directly phosphorylate ampars ( camkii ) or to regulate ca - stimulated gene expression [ 3436 ] . although the important role of camks in hebbian synaptic plasticity has been extensively studied [ 32 , 37 ] , their involvement in homeostatic regulation has not been studied until recently . in a cultured cortical neuron , ibata et al . they show that 4  hr selective inhibition of somatic activity induces a rapid , global upscaling in mepsc amplitude and postsynaptic ampars in the inhibited neuron . the quantity of surface ampars is imaged and measured by live imaging of eyfp - tagged glua2 subunits expressed in dissociated rat cortical neurons . this homeostatic response results from a drop in somatic ca level and reduced camkiv activation . coexpression of a dominant - negative form of camkiv ( dncamkiv ) with eyfp - glua2 for 24  hrs mimics the ttx effect on mepscs . in another study , goold and nicoll channelrhodopsin ( chr2 ) is expressed in hippocampal ca1 neurons in brain slices for 2 - 3 days , and a light train at 3  hz is applied to stimulate the transfected neurons for 24  hrs . this lasting activation leads to a homeostatic depression of both ampar- and nmdar - mediated currents , and a reduction in surface expression of ampars and nmdars . camkiv , activated by ca influx through the l - type voltage - gated calcium channels , plays a key role in the light activation - induced responses ; expression of a dominant - negative camkiv blocks the homeostatic downregulation in ampars and nmdars . together , these studies indicate an important role for camkiv in cell - autonomous bidirectional homeostatic plasticity . in addition to camkiv , other camk members , like camkii , may also participate in homeostatic regulation . show that - and camkii are inversely regulated by neuronal activity and they also have opposite effects on mepscs . in cultured hippocampal neurons , activity deprivation by 24-hour conversely , chronic hyperactivity by 24-hour bicuculline treatment significantly increases camkii and decreased camkii levels . overexpression of camkii in hippocampal neurons significantly decreases , while camkii increases , the amplitude of mepscs after 2030  hrs . recently , another study shows that knockdown of camkii in hippocampal neuron blocks nbqx - induced homeostatic increase in synaptic ampar expression whereas camkii overexpression increases synaptic ampar levels . these findings suggest an important role of camkii in the expression of homeostatic synaptic response . brain - derived neurotrophic factor ( bdnf ) is broadly involved in many physiological processes in the developing or mature nervous system . once released , bdnf binds to the trkb receptors to trigger a series of downstream signaling pathways . given its positive role in neuroprotection , bdnf is considered valuable in the management of several neurological diseases such as huntington 's disease , epilepsy , and alzheimer 's disease . the chronic presence of bdnf enhances synaptogenesis   and controls synaptic transmission and plasticity at both glutamatergic and gabaergic synapses . in cultured cortical neurons derived from rat visual cortex , application of exogenous bdnf blocks activity deprivation - induced homeostatic upscaling , whereas bdnf depletion by high - affinity trkb receptors mimics inactivity - induced upward homeostatic change in mepscs . bdnf has been found to affect mepscs differentially in pyramidal neurons and interneurons . in cultured rat visual cortical neurons , bdnf attenuates the ttx - induced homeostatic increase in mepsc amplitudes at synapses formed onto pyramidal neurons , but enhances the ttx effect at synapses formed onto interneurons . intriguingly , in cultured hippocampal neurons , bdnf treatment enhances mepscs in excitatory synapses , likely due to enhanced ampar trafficking [ 45 , 46 ] , which is inconsistent with its role in homeostatic downregulation . recently , several studies show that bdnf treatment enhances ampar trafficking to glutamatergic synapses , both in vitro and in vivo [ 47 , 48 ] . in cultured hippocampal neurons , caldeira et al . show that elevated ampar trafficking by bdnf is receptor subunit specific . surface expression of glua1 is preferentially increased in the first 30  min of bdnf incubation , leading to the formation of calcium - permeable , glua1 homomeric ampars . at a later stage enhanced ampar synaptic delivery requires the activation of trkb receptors and the pi3k - akt pathway , most likely through phosphorylation of the glua1 c - terminal at s831 . in addition to its role in ampar trafficking , bdnf has also been shown to function as a retrograde messenger released from the postsynaptic site to alter presynaptic activity in an activity - dependent manner [ 50 , 51 ] . inhibition of ampar activity by nbqx for 24  hrs or cnqx for 3  hrs homeostatically increases the frequency and amplitude of mepscs . removal of bdnf by adding high - affinity trkb receptors or bdnf antibodies and pharmacologically blocking of the down - stream function of bdnf all lead to an abolishment of the enhanced presynaptic response without affecting postsynaptic activity . consistently , application of bdnf itself induces similar presynaptic changes as produced by ampar inhibition . the phosphoinositide 3-kinase- ( pi3k- ) akt pathway is wellknown for its involvement in ampar trafficking , synaptic plasticity , and memory consolidation both in vivo and in vitro [ 52 , 53 ] . for instance , protein synthesis and ampar insertion in late - phase ltp requires pi3k pathway activation [ 5355 ] . in vivo , activation of the pi3k pathway is also required for the maintenance of ltp in hippocampal ca1 neurons . consistent with its important role in ltp , pi3k is implicated in memory consolidation as well . however , in contrast to abundant evidence about its role in hebbian synaptic plasticity , involvement of pi3k signaling in homeostatic synaptic plasticity remains unclear . first , the pi3k - akt pathway is known to induce protein synthesis   and ampar membrane insertion [ 54 , 56 ] , processes known to occur in homeostatic ampar upregulation . second , both tnf and bdnf , the two major factors that mediate homeostatic plasticity , activate the pi3k - akt pathway and increase ampar expression at the postsynaptic surface [ 28 , 41 , 49 ] . in cultured hippocampal neurons , inhibition of presynaptic activity by overexpression of an inward - rectifier potassium channel kir2.1 results in a significant increase in postsynaptic ampars . consistent with this finding , a recent study also demonstrates the pi3k - akt pathway as a mediator of global homeostatic plasticity . presenilin 1 ( ps1 ) is an integral component of -secretase that is closely linked to alzheimer 's disease [ 57 , 58 ] . ps1 activates the pi3k - akt pathway by promoting the formation of akt - activating cadherin / pi3k complexes , pratt et al . have found that the global homeostatic upscaling of mepscs induced by prolonged ttx treatment is impaired in cultured hippocampal neurons derived from ps1 knockout mice , suggesting a possible involvement of pi3k cascade . in support of this possibility , overexpression of constitutively active akt rescues impaired global synaptic scaling in ps1 knock - out neurons without affecting mepsc amplitude in wild - type neurons . together these studies indicate the necessity of the pi3k - akt pathway in homeostatic upregulation . integrins and neuronal ( n)-cadherin/-catenin are cell adhesion molecules ( cams ) that are expressed at synapses and possess important functions in synapse formation , differentiation , and maturation , as well as synaptic plasticity [ 61 , 62 ] . malfunction of cams can produce severe problems in the nervous system including abnormal spine morphology , decreased synapses quantity , and impaired cognitive function [ 61 , 6366 ] . n - cadherin is a ca - dependent homophilic adhesion protein that is present at both pre- and postsynaptic membranes . it signals through rho - family gtpases , via catenins , to control dendritic spine morphology and motility . the n - cadherin/-catenin complex regulates the surface expression and intracellular trafficking of ampars by directly interacting with ampars [ 6971 ] . the n - terminal domain of n - cadherin physically interacts with the glua2 subunit of ampars at the extracellular space , promoting spine growth and synaptic transmission . nuriya and huganir have shown that overexpression of wild - type n - cadherin in cultured hippocampal neurons can specifically increase the postsynaptic ampar expression . by targeting ampars during endocytosis and exocytosis at the postsynaptic surface , the n - cadherin/-catenin complexes also regulate the bidirectional homeostatic responses of neural activity . show over - expression of a dominant - negative mutant of n - cadherin compromises the chronic up - scaling of quantal ampar responses induced by ttx treatment , whereas selective deletion of -catenin in cultured hippocampal neurons eliminates the global homeostatic regulation [ 72 , 73 ] . in addition to their roles in conventional postsynaptic homeostatic regulation , a recent study has demonstrated a role for n - cadherin/-catenin in the compensatory adaptation of presynaptic release to chronic activity deprivation by ttx treatment . have found overexpression of dominant - negative n - cadherin ( dn - ncad ) in cultured hippocampal neurons significantly reduces the basal presynaptic release probability , but does not change the homeostatic upregulation of presynaptic release . in contrast , ablation of -catenin has no effect on basal presynaptic release but completely abolishes the homeostatic increase in presynaptic release induced by chronic activity deprivation by ttx treatment . integrins are heterodimeric transmembrane molecules of which many subunits are expressed in the central nervous system . previous studies have revealed multiple roles for integrins in synaptogenesis , synaptic transmission , and plasticity , as well as memory formation [ 65 , 74 ] . 3 integrin regulates synaptic strength by modulating the surface expression of ampars in a subunit - specific manner . over - expression of 3 integrin in dissociated hippocampal neurons enhances ampar surface expression via suppression of rap1 , a pathway known to negatively control ampar trafficking during synaptic plasticity by enhancing endocytosis of glua2 subunits . because tnf , an important molecule in homeostatic plasticity , causes an elevated cell - surface expression of 3 integrin , it suggests a possible involvement of 3 integrin in homeostatic response by regulating ampar trafficking . consistent with this hypothesis , a recent study shows that 24  hr ttx or bicuculline treatment causes a corresponding increase or decrease of surface 3 integrin without affecting 1 integrin . prolonged ttx treatment enhances the surface 3 integrin to a level similar to that by tnf treatment . more directly , overexpression of dominant - negative 3 integrin , ct3 , completely eliminates the ttx - induced global homeostatic up - scaling of mepscs and synaptic ampar expression . under physiological conditions most ampars contain at least one glua2 subunit and allow only sodium influx to depolarize membrane potential during synaptic activation . when ampars are composed without glua2 subunits , the receptor channel will permeate calcium in addition to sodium . due to a channel blockade by intracellular polyamine at positive membrane potential , currents from cp - ampars show a signature feature of inward rectification in the current - voltage relationship . it has been found that the expression of glua2-lacking receptors is regulated by development , synaptic activity , or pathological challenges such as ischemia or amyotrophic lateral sclerosis ( als ) . in the early postnatal ages , cortical pyramidal neurons have higher rectification in ampar - mediated synaptic currents , which diminishes in more mature animals , indicating a developmental switch in ampar composition and calcium permeability . by providing an unconventional source of calcium other than nmdar or calcium channels , glua2-lacking ampars may play an important role in synaptic plasticity . indeed , in the expression of hippocampal ltp , glua2-lacking ampars are first incorporated into the synapse , which will then be replaced with glua2-containing receptors . in cerebellar stellate cells which normally contain glua2-lacking ampars , high - frequency presynaptic activity induces a calcium - dependent increase in synaptic insertion of glua2-containing ampars . these findings strongly indicate the presence of a self - regulating mechanism by which cp - ampar - mediated calcium flux triggers recruitment of normal glua2-containing ampars to synapses . activity deprivation has been shown to induce inward rectification in the current - voltage relationship of ampar - mediated current , suggesting the formation of glua2-lacking , calcium - permeable ampars [ 19 , 8183 ] . consistently , following treatment paradigms for homeostatic plasticity , ampar - mediated currents become sensitive to cp - ampar - selective antagonists philanthotoxin-433 ( phtx ) or naspm [ 19 , 20 , 8183 ] . interestingly , multiple signaling molecules that are involved in homeostatic synaptic plasticity including tnf , retinoic acid , arc / arg3.1 , and 3 integrin are capable of causing imbalanced glua1 and glua2 regulation and cp - ampar expression . the homeostatic factor tnf is known to cause rapid membrane insertion of glua2-lacking ampars [ 28 , 84 ] . in retinoic acid - mediated synaptic scaling , the increase in ampar surface expression is glua1 specific , and the homeostatic response in mepscs is abolished by suppression of cp - ampars . an unbalanced regulation in ampar subunits is also observed in arc / arg3.1-mediated homeostatic regulation . knockout of arc / arg3.1 results in a typical synaptic scaling of ampar - mediated mepscs . interestingly , arc / arg3.1 knockout neurons reveal a significant increase in glua1 surface expression , whereas surface glua2 shows no change , implicating membrane addition of glua2-lacking ampars . in addition , disruption of 3 integrin induces internalization of glua2 , but not glua1 subunits , resulting in glua2-lacking ampars at the cell surface . in our own study , we find that homeostatic regulation by single synaptic suppression is abolished by the application of phtx , indicating the requirement of cp - ampar signaling . interestingly , the blockade of homeostatic plasticity is observed only when phtx is applied at the early stage of activity deprivation , indicating that cp - ampars are needed for the initiation , but not maintenance , of homeostatic synaptic regulation . arc / arg3.1 is an immediate - early gene product whose abundance at synapses is strictly coupled with neural activity level . strong synaptic activation will dramatically enhance the expression of arc / arg3.1 in dendrites and spines while synaptic suppression decreases its expression [ 86 , 87 ] . arc / arg3.1 is broadly involved in different forms of synaptic plasticity including both hebbian plasticity and homeostatic regulation . find that arc / arg3.1 controls synaptic transmission strength by negatively regulating the surface expression of ampar expression at the post - synaptic surface . over - expression of arc / arg3.1 in hippocampal neurons promotes the endocytosis of glua2/3 containing ampars as well as the reduction of ampar - mediated synaptic current amplitude . / arg3.1 knockout mice , ampars show markedly reduced endocytosis and enhanced steady - state surface expression [ 85 , 89 ] . shepherd et al . also find that arc / arg3.1 is involved in bidirectional homeostatic regulation of neural activity via regulating ampar internalization and endocytosis . in primary neuronal culture , synaptic expression of arc / arg3.1 is enhanced after chronic activity deprivation , while over - expression of arc / arg3.1 blocks the global synaptic up - scaling of mepscs and ampars induced by chronic activity deprivation . conversely , in cultured hippocampal neurons from arc / arg3.1 knockout ( ko ) mice , either global up- or down - homeostatic scaling induced by prolonged ttx or bicuculline treatment is impaired . together these studies demonstrate strong evidence about the involvement of arc / arg3.1 in the bi - directional homeostatic regulation of neural activity through regulation of the trafficking of ampars . it has also been shown that arc / arg3.1 directly interacts with endophilin and dynamin to form post - synaptic endosomes which facilitate the endocytosis of ampars . in addition to global regulation , arc / arg3.1 also mediates local homeostatic plasticity at individual synapses . using kir2.1 paradigm , bque et al . show that homeostatic upregulation of mepscs is abolished in cultured cortical pyramidal neurons derived from arc knock - out mice . retinoic acid ( ra ) , also known as vitamin a , is best known for its role in regulating the development of the nervous system , including neurogenesis and neuronal differentiation [ 91 , 92 ] . in a recent study , show that 24  hr ttx + apv treatment , a homeostatic paradigm that induces global synaptic upscaling of mepscs and ampars , significantly enhances the synthesis of ra in both cultured hippocampal neurons and brain slices . application of ra rapidly increases the strength of synaptic transmission mainly through an increase in surface expression of ampars . effects of ra are translation , but not transcription dependent , and are occluded by ttx + apv treatment , indicating an involvement of ra signaling in homeostatic plasticity . in addition , ampar upregulation by apv + ttx treatment is subunit specific , with a preferential increase in glua1 over glua2 , leading to the production of glua2-lacking , calcium - permeable ampars . a recent study from the same group indicates a role of the fragile - x mental retardation protein ( fmrp ) in ra - induced glua1 local translation . fmrp is a dendritic rna - binding protein encoded by the fmr1 gene that is involved in the downregulation of local mrna translation and protein synthesis [ 95 , 96 ] . in fmr1 knockout mice , both ttx + apv - induced ampar homeostatic upregulation and ra - induced local ampar synthesis are impaired . over - expression of wt - fmrp but not mutant fmrp in fmr1 knockout neurons therefore , via the effect of fmrp , homeostatic regulation may be implicated in the neurodysfunction in fragile x syndrome . protein interacting with c - kinase 1 ( pick1 ) is a pdz domain - containing protein that directly interacts with the glua2 subunit of ampars [ 97 , 98 ] . pick1 also directly interacts with the ampar adaptor protein , abp / grip to regulate ampar trafficking . the importance of pick1 in hebbian synaptic plasticity , especially in ltd , has been well documented both in vivo and in vitro [ 100 , 101 ] . pick1 influences synaptic plasticity by stimulating ampar internalization [ 102 , 103 ] . for instance , in pick1 knockout mice , nmda - induced ltd is abolished in hippocampal neurons due to disrupted internalization , recycling , and retention of glua2-containing ampars [ 100 , 101 ] . by interacting with the glua2 subunit , pick1 plays a key role in the plasticity involving the calcium - permeable , glua2-lacking ampars . in a specific type of ltp induced by cocaine exposure at the glutamatergic synapses of dopaminergic neurons in the ventral tegmental area since calcium - permeable ampars serve as an important signal in homeostatic scaling , these findings imply a regulatory role for pick1 in homeostatic regulation . indeed , a recent study using cultured cortical neurons showed that pick1 specifically mediates the ttx - induced global up - scaling of mepscs and synaptic ampars , without affecting bicuculline - induced downward homeostatic regulation . in cultured cortical pyramidal neurons derived from pick1 knockout mice , while the number of synaptic ampars are increased , ttx - induced mepsc up - scaling is occluded due to altered ampar subunit composition and aberrant receptor trafficking . ups uses a small protein of 76 amino acids , namely , ubiquitin , to mark proteins destined for degradation . following ubiquitination , a polyubiquitin chain is attached to the lysine residues of the target protein so that it can be recognized by the degradation machinery proteasome . ups components are widely distributed in a neuron from the soma to dendrites and synapses [ 107 , 108 ] . it regulates many important synaptic functions including synapse development , maturation , and synaptic plasticity . given the importance of proper protein turnover in cells , ups dysfunction is implicated in the pathogenesis of many neurodegenerative diseases . ups function is closely related to the neural activity levels [ 108 , 111 ] to control the post - synaptic proteins composition including psd-95 [ 112 , 113 ] and ampar - associating protein grip . ampars are directly subjected to ubiquitination , leading to their internalization and degradation [ 115117 ] . several recent studies have shown the ups activity is also involved in the regulation of both global and local homeostatic plasticity . show that application of a proteasome inhibitor , lactacystin , for 24  hrs in cultured hippocampal neurons causes a global up - scaling of mepscs and ampar expression , which mimics and occludes the ttx - induced homeostatic synaptic response . in addition to the pharmacological study , expression of a mutant ubiquitin which inhibits protein ubiquitination by blocking ubiquitin chain elongation produces similar effects as prolonged lactacystin treatment . in another recent study , hou et al . utilize light - controlled glutamate receptor ( liglur ) to selectively activate individual synapses in cultured hippocampal neurons . single synaptic activation leads to homeostatic downregulation of postsynaptic ampar abundance as a consequence of enhanced ampar internalization and degradation . this activity - dependent homeostatic ampar alteration is accompanied by a recruitment of polyubiquitinated proteins and ampar e3 ligase nedd4 [ 115 , 116 , 120 ] and is blocked by the application of proteasome inhibitors , strongly indicating a key role of the ups in hyperactivity - induced homeostatic plasticity . homeostatic synaptic regulation is one of the fundamental forms of plasticity serving to maintain the functional stability of the nervous system from a single synapse to an entire neural network . at a cellular level , homeostatic response will keep the firing rate within a physiological range , and at individual synapses , it prevents synaptic activity from running away to the extremes . although a change in ampar trafficking and synaptic accumulation has been considered the primary mechanism , homeostatic regulation of neuronal activity can also be expressed via regulating other cellular components such as presynaptic transmitter release , cell intrinsic excitability , synaptic connectivity , and the relative balance between excitation and inhibition . potentially , dysfunction of homeostatic regulation will lead to a shift in basal neuronal and synaptic activity , and altered sensitivity to stimuli . consequently , super up - scaling could cause epileptic activity and excitotoxic cell death , whereas abnormal downscaling would result in neural suppression and impaired cognitive function . therefore , homeostatic plasticity may play a crucial role in the pathogenesis of multiple neurological disorders including neurodegenerative diseases , which , we expect , will continue to be a topic of investigation for the foreseeable future .
homeostatic synaptic plasticity is a negative - feedback response employed to compensate for functional disturbances in the nervous system . 
 typically , synaptic activity is strengthened when neuronal firing is chronically suppressed or weakened when neuronal activity is chronically elevated . at both the whole cell and entire network levels , activity manipulation leads to a global up- or downscaling of the transmission efficacy of all synapses . 
 however , the homeostatic response can also be induced locally at subcellular regions or individual synapses . 
 homeostatic synaptic scaling is expressed mainly via the regulation of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ( ampar ) trafficking and synaptic expression . here 
 we review the recently identified functional molecules and signaling pathways that are involved in homeostatic plasticity , especially the homeostatic regulation of ampar localization at excitatory synapses .