huntington s disease ( hd ) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene [ 14 ] . initially , patients manifest uncontrolled , choreic  dance - like  movements . this hyperkinetic phase is followed by a hypokinetic phase where purposeful movement is difficult . consistent with the motor symptoms , postmortem studies of hd brains have found the basal ganglia to be a major site of pathology , in spite of the widespread expression of mutant huntingtin ( mhtt ) [ 2,68 ] . the earliest neuronal pathology in the basal ganglia is in the caudate and putamen ( collectively referred to the striatum in rodents ) . less profound pathology also is found in the cerebral cortex and thalamus , both structures that innervate the striatum . the biphasic progression of symptoms in hd patients  and in many animal models  is consistent with the view that principal striatal gabaergic spiny projection neurons ( spns ) are not uniformly susceptible to mhtt . striatal spns can be divided into two roughly equally sized groups that differ along a number of dimensions , including peptide expression and axonal projection . the first signs of pathology in hd patients are in one of these groups : indirect pathway spns ( ispns ) ; ispns anchor the basal ganglia network that suppresses contextually inappropriate movements . later in the disease , direct pathway spns ( dspns ) that express substance p are affected ; dspns anchor the basal ganglia circuit that promotes contextually appropriate movements . thus , hd neuropathology and symptoms align nicely with what is known about the functional circuitry of the striatum . support for this hypothesis comes primarily from the fact that intrastriatal injection of the glutamate receptor agonist quinolinic acid ( an nmdar agonist ) mimics many characteristics of hd in rodents . the proposition that nmda receptors ( nmdars ) drive neuronal loss in hd also is consistent with a large literature showing how this might happen . however , more recent work has cast doubt on this theory . as outlined below , studies in animal models of hd suggest that there is a progressive loss of excitatory corticostriatal glutamatergic input to spns with advancing age , rather than a progressive growth of this input . in addition , there is evidence that the other major excitatory glutamatergic input to spns from the thalamus is also lost . while these observations do nt unequivocally kill the excitotoxicity hypothesis , they make it less plausible . as the excitotoxicity hypothesis has fallen in favor , another hypothesis has risen to prominence . several lines of study suggest that something goes awry with cortical trophic support for the striatum . brain derived neurotrophic factor ( bdnf ) is synthesized by cortical pyramidal neurons innervating the striatum , transported to the striatum and released . bdnf activation of trkb receptors on spns is necessary to maintain normal dendritic and synaptic function [ 1719 ] . what follows , we briefly outline recent developments that have led to our current opinion about striatal excitatory synaptic dysfunction in hd . the review is not all inclusive and readers are referred to a number of other recent reviews that cover similar or complementary aspects of the expansive hd literature [ 2024 ] . since the genetic locus of hd was identified in 1993 , a number of genetic models have been developed in mice . these models differ significantly in their genetic strategy , have different rates of progression and types of neuronal pathology ( see reviews by ) ( fig . 1 ) . the first models expressed an exon 1 fragment of mhtt with a large number ( 110150 ) of cag repeats ( e.g. , the r6/2 model ) . these mice are rapidly progressing , manifesting motor symptoms within a few weeks of birth and die prematurely . subsequently , full length mhtt models were constructed with varying cag repeat lengths ( yac72 ( 72 repeats ) , yac128 ( 128 repeats ) and bachd ( 97 repeats ) . these models have slower disease progression with a clear dependence upon expansion length and gene dosage [ 2729 ] . in the last few years , more biologically faithful knock - in models have been created ( q140 , zq175 lines ) . do these models mimic the human disease ? as discussed above , humans transition through a hyperkinetic ( choreic ) and then a hypokinetic state . biphasic behavioral changes like this are seen in many hd models , but not all . in particular , only some slowly progressing models manifest a hyperkinetic phase , whereas all have a hypokinetic phase . the short repeat fragment model ( r6/1 ) and full - length yac72 , yac128 , q94 and q140 models have an early hyperkinetic phase before ultimately becoming hypokinetic . the absence of a hyperkinetic phase in the zq175 model is puzzling , as it was derived from q140 model . one possible explanation for the discrepancy is that mhtt does not affect brain circuits controlling movement sequentially , but rather affects them in parallel . if the rate of disease progression within each of these circuits is independently affected by the genetic approach used to introduce mhtt , then the duration of each motor phase could vary . the early hyperkinetic phase should be the most sensitive to this kind of parallel process . for example , let s suppose that the hyperkinetic phase is dependent upon reduced activity in the indirect pathway and the hypokinetic phase is dependent upon reduced activity in the direct pathway . a slower rate of progression in the direct pathway than the indirect pathway would yield the human pattern of staging . but if the rates of progression are similar is some models ( e.g. , bachd ) , then the hyperkinetic phase would be absent . since no one mouse model perfectly recapitulates all aspects of the human hd condition , which model is the best ? in principle , the heterozygous cag140 and zq175 models most accurately model the human condition as they place a single copy of full length mhtt in its native genomic locus ; these models display a progressive behavioral phenotype and recapitulate many synaptic and anatomical pathologies present in more rapidly progressing models ( fig . however , it must be acknowledged that the choice of the most appropriate model for a particular study will depend upon many factors . for years , the pathology in hd was envisioned to be a consequence of glutamatergic excitotoxic damage to spns , as injection of nmda receptor ( nmdar ) agonists within the striatum produced a pattern of pathology resembling that found in hd brains . but the ability of nmdar agonists to phenocopy striatal changes does not mean that they mimic pathogenesis . was there evidence that glutamatergic signaling in the striatum was altered in genetic models of hd ? the first direct physiological evidence that something was changed came from the analysis of spontaneous excitatory events in ex vivo brain slices from the r6/2 hd mouse ; in these studies , the frequency of spontaneous synaptic glutamate release onto spns increased and then decreased ( fig 1 ) . without knowing the identity of sampled spns ( dspns or ispns ) or the source of released glutamate , little can be inferred about why this happened or what it might mean for the striatal circuitry , but what these studies do show is that glutamatergic signaling is changing in hd models . does the glutamatergic input to both ispns and dspns change ? recall that in humans , ispns appear to be the most vulnerable to the disease process . the loss of ispn functional integrity has long been thought to be responsible for the hyperkinetic features of early stage hd , as ispns anchor the indirect pathway responsible for movement suppression . more recent studies have begun to address this question by crossing hd genetic models with bac transgenic mice in which dspns or ispns express green fluorescent protein ( gfp ) [ 3537 ] . using this strategy levine s group suggested that the early increase in spontaneous glutamate epsc frequency was specific to dspns , which would increase direct pathway excitability and promote hyperactivity . however , andre et al . also showed that evoked glutamatergic responses were substantially larger in ispns in young hd models , but dspn responses were normal . these results suggest that early in the evolution of the disease , there is a complex set of pre- and post - synaptic changes taking place at spn glutamatergic synapses , which might not map cleanly to the early and late motor symptoms of hd . nevertheless , these studies show that synaptic glutamate receptor function is not changing in a way that is consistent with an excitotoxicity model of hd . out here for the excitotoxicity model is that it does not specify that synaptic glutamate receptors are driving pathology . in the last decade it has become clear that while synaptic nmdars promote neuronal viability , extrasynaptic nmdars are coupled to signaling cascades that promote degeneration and death . in a landmark paper , milnerwood and raymond demonstrated that the abundance of extrasynaptic glun2b - containing nmdars rises in hd spns . subsequently , they have shown that the insertion of extrasynaptic nmdars is regulated by calpain- and striatal enriched protein tyrosine phosphatase ( step )   in aged yac128 mice ( fig . moreover , the elevation in extrasynaptic nmdars appears to occur first in ispns , then ultimately spreads into both spn types , establishing a parallel with the evolution of pathology in humans . the proposition that there is a progressive engagement of extrasynaptic nmdars driving pathology is also consistent with changes in astrocytic function seen in the hd models . clearance of glutamate from the synaptic cleft is controlled by astrocytic uptake through transporters . in symptomatic hd mice , astrocytic expression of glutamate transporter 1 ( glt1 ) is down - regulated . in principle 2 ) . in addition , recent work in aged r6/2 hd mice has shown that astrocytes down - regulate the expression of a key k channel ( kir4.1 ) , resulting in an elevation in extracellular k concentration . elevating extracellular k should depolarize spns and make it easier to remove the mg block of nmdars . thus as plausible as this scenario seems , work in the last year has cast doubt on the proposition that extrasynaptic nmdars are driving late stage striatal pathology in hd . gladding et al ( 2014 ) found that while intrastriatal injection of quinolinate ( an nmdar agonist ) induces neuronal death in young presymptomatic ( 6 week ) yac128 mice , the same injection into aged ( 1 year ) yac128 mice had little effect . the resistance to nmdar excitotoxicity in the older hd mice appeared to be due to an attenuation of the ability of extrasynaptic nmda receptors to activate pro - apoptotic p38 mitogen - activated protein kinase ( p38 mapk ) . in young mice , extrasynaptic nmdars robustly engaged p38 mapk , whereas in older hd mice , this linkage seemed to be attenuated . although this work suggests that nmdars are not driving hd pathology , the issue is not resolved . argues that striatal expression of glun3a in very old ( 16 month ) yac128 mice is critical to late stage synaptic dysfunction and neurodegeneration . there is a significant body of literature suggesting that mhtt impairs the ability of cortical pyramidal neurons to provide the striatum with needed bdnf , leading to striatal there is no question that cortical bdnf expression and axonal transport can be impaired by mhtt . however , these studies have relied largely upon over - expression of mhtt in cell culture models , not in vivo or ex vivo approaches in mouse hd models . those studies that have been done in mouse models that support this conclusion have focused upon bdnf mrna abundance assays that have used less than optimal strategies for quantitation . another prickly issue with this model is that both dspns and ispns express the receptor for bdnf  trkb receptors    and receive overlapping cortical inputs . how then , if non - cell autonomous factors are driving striatal hd pathology , does selective vulnerability come about ? recent work using very different approaches argues that there are corticostriatal bdnf signaling deficits in hd models , but that these deficits are in the postsynaptic response to bdnf , not its delivery , release or binding to trkbrs . in 6 month old bachd and heterozygous zq175 knock - in mice ( before striatal cell loss ) neither cortical nor striatal bdnf mrna or protein was abnormal . however , trkbr activation of akt  a key signaling kinase in prosurvival pathways  was impaired . to pinpoint why this was the case , a functional assay for trkbr signaling was developed using the fact that corticostriatal long term potentiation ( ltp ) requires spn trkbr signaling ( fig 2 ) . this led to the conclusion that trkbr signaling through phosphoinositide-3 kinase ( pi3k ) was blunted specifically in hd ispns due to up - regulation of phosphatase and tensin homolog deleted on chromosome 10 ( pten ) . it also was found that p75 neurotrophic factor receptor ( p75ntr ) signaling was necessary for pten - mediated attenuation of trkbr signaling . why pten is up - regulated initially in ispns remains to be determined ( fig 2 ) , but one intriguing possibility is that d2 receptors , which are expressed by ispns and not dspns , are involved , as d2 receptors have been shown to elevate the engagement of several downstream targets of p75ntrs . whether this turns out to be the mechanism or not , these studies support the proposition that neuronal phenotype is a determinant of the staging of hd pathology . a deficit in ispn trkbr signaling and ltp induction is consistent with the progressive attenuation of corticostriatal glutamatergic signaling described in hd models ( fig . while the earliest deficits in striatal trkbr signaling have been found in ispns , it is likely that as the disease progresses , this deficit will spread to dspns . it is of some note that hd patients have a lower incidence of cancer and pten ( the proximal culprit in impaired trkbr signaling ) is a tumor suppressor ; this suggests that mhtt might ultimately induce pten up - regulation broadly . not only might this lead to impaired trkbr signaling in dspns , but the deficit should appear in cortical pyramidal neurons and neurons in other regions of the brain . an important implication of these findings is that delivery of small molecule trkbr agonists is unlikely to be effective in hd . rather , targeting p75ntr signaling should be more effective as well as less burdened by side - effects , as this receptor is developmentally downregulated and has a restricted tissue distribution . it also should be remembered that the cerebral cortex and striatum form part of a richly connected network involved in movement and thought control . it is impossible to affect one component of this network without affecting other components ( fig 3 ) . for example , expression of mhtt in a discrete cortical neuron populations induces pathology in neighboring neurons . since bdnf production and release are activity dependent , deficits in corticostriatal signaling are very likely to ultimately lead to deficits in bdnf signaling within other components of the circuit , most importantly the cerebral cortex . for some time it has been thought that gabaergic input to spns increased in hd models , nominally compensating for their increased intrinsic excitability . this conclusion was based upon a reported increase in the frequency of spontaneous inhibitory postsynaptic currents ( sipscs ) in a random sample of spns in symptomatic r6/2 , yac128 and cag140 hd models . subsequent work in bac - egfp transgenic mice found that the increase occurred first in dspns and then later in ispns . spns have gabaergic synapses arising from other spns and a heterogeneous group of interneurons ( there are at least 3 classes ) . because spontaneous ipscs are a mixture of miniature ipscs ( whose frequency depends upon terminal release probability ) and spike - drivien ipscs , there is no way of knowing which circuit elements are driving changes in sipsc frequency or why . recent work using another approach has challenged the general notion that gabaergic inhibition of spns is increased in hd models . found that in both r6/2 and zq175 models , gabaergic responses evoked by minimal local stimulation were reduced in spns . the reduction was attributable to an up - regulation in mglur5 mediated endocannabinoid ( ecb ) production , resulting in presynaptic cb1 receptor activation and suppression of gaba release . although the identity of the presynaptic axons was not determined , it is not unreasonable to make the conjecture that they were collaterals from neighboring gabaergic spns given the strong cb1r mediated suppression of gaba release . .   found that collateral connectivity between spns was attenuated in the r6/2 model . in this same study , the authors found that optogenetic activation of fast - spiking interneurons ( fsis ) evoked larger responses in hd spns . stimulation of another major interneuron input to spns  from pltsis  yielded similar amplitude responses , but the spontaneous activity of these interneurons was elevated in hd brain slices . taken together , these studies suggest that gabaergic input to spns from interneurons is elevated in the hd striatum , whereas that arising from collaterals is diminished . as both fsis and pltsis appear to be part of a corticostriatal feedforward inhibitory circuit , the changes described could serve to limit the duration of the striatal response to cortical glutamatergic excitation . in contrast , collateral feedback between spns would be expected to limit the spatial dimensions of the cortically evoked striatal activity . that said , there are some fundamental unknowns in this equation . one is that it is far from clear whether it is appropriate to characterize gabaa receptors as inhibitory . at rest , kir2 k channels dominate the spn conductance profile ( though there is evidence their somatic density may be reduced in hd spns ) , holding the membrane potential in a although it has not been determined rigorously in adult spns , the cl reversal potential is sure to be more depolarized than this , probably in the range of 65 to 70 mv . the shunting effect of open gabaa receptors could counter - balance this effect to some extent when there is temporally coincident excitatory input . but this effect is short - lived and because the local depolarizing effect of gaba should globally collapse the electrotonic structure of spns , glutamatergic inputs that trail the gabaergic input should be amplified . this could bring nmda receptors into a voltage range where mg block is less potent . sorting how these interactions occur in spn dendrites still faces technical hurdles but advances like multi - color opsins   should make profitable study feasible soon . another unresolved issue is the impact of tonic , extrasynaptic gabaa receptor currents in the hd models . tonic currents are prominent in spns   and help set the membrane potential and input resistance of dendrites  key determinants of synaptic integration . neurogliaform gabaergic interneurons , which have not been examined in hd models to date , appear to exert a strong influence on these receptors . also , if there is astrocytic dysfunction in hd , gaba could easily  overflow from synaptic sites to these receptors . although recent studies provide a rich working framework for understanding how mhtt alters the moment - to - moment activity in the corticostriatal network , there are fundamental questions about long - term plasticity of synapses that remain unanswered . for example , is corticostriatal ltp the only form of synaptic plasticity altered in the hd striatum ? the best understood form of synaptic depression at both cortical glutamatergic and intrastriatal gabaergic synapses requires postsynaptic group i metabotropic glutamate receptor ( mglur ) mediated production of endocannabinoids ( ecbs ) , which then diffuse to the presynaptic terminal , bind to presynaptic cb1 receptors ( cb1rs ) , and reduce neurotransmitter release probability [ 7274 ] . one of the earliest molecular changes in hd patients is a decrease in cb1r expression in both the striatum and cortex . it is unknown if corticostriatal synaptic depression is altered in hd , but recent work showed that genetically correcting cb1r down - regulation in spns rescues axospinous ( largely corticostriatal ) synapse loss in hd mice suppression of spn collateral gaba release might engage homeostatic mechanisms to increase glutamatergic innervation ( leading to more spines ) . this makes sense if gabaergic synapses were excitatory . as mentioned above , this is not so far - fetched since spns rest about 20 mv more hyperpolarized than the cl reversal potential ( gabaa receptors are cl permeable channels ) . in this scenario , suppression of gabaergic signaling could lead to spn hypoexcitability , triggering homeostatic up - regulation of glutamatergic synapses . finally , though striatal glutamatergic hypoexcitability is a common theme among late stage hd models , it is far from certain that this hypoexcitability is entirely synaptic in origin . for example , dendritic morphology and ion channel composition exquisitely shape how spns integrate glutamatergic inputs . alterations in either of these parameters might diminish the response to activation of glutamatergic synapses . although spn dendrites are too small to directly record , two photon laser scanning microscopy , optogenetics and two photon uncaging techniques make these regions accessible to investigation . these approaches should make the role of intrinsic mechanisms in hd pathogenesis clearer in the near future . the development of new mouse models and tools for analyzing brain networks and synapses has led to fundamental new insights into the mechanisms driving hd pathogenesis . this is most evident in our understanding of how mhtt affects the corticostriatal network . in the last few years , the field has moved from thinking that striatal pathology in hd was driven by excitotoxic mechanisms to the view that , if anything , it is a hypoexcitability disorder driven by impaired corticostriatal signaling . although there remain fundamental gaps in our understanding of synaptic dysfunction in hd , the tools at our disposal should accelerate progress toward filling these gaps . with that understanding
huntington s disease ( hd ) is a progressive neurodegenerative disorder that profoundly impairs corticostriatal information processing . 
 while late stage pathology includes cell death , the appearance of motor symptoms parallels more subtle changes in neuronal function and synaptic integration . because of the difficulty in modeling the disease and the complexity of the corticostriatal network , understanding the mechanisms driving pathology has been slow to develop . in recent years 
 , advances in animal models and network analysis tools have begun to shed light on the circuit - specific deficits . 
 these studies have revealed a progressive impairment of corticostriatal synaptic signaling in sub - populations of striatal neurons , turning classical excitotoxicity models of hd upside down . disrupted brain derived neurotrophic factor signaling appears to be a key factor in this decline .