Corticostriatal Dysfunction Research Articles

VPS13A knockdown impairs corticostriatal synaptic plasticity and locomotor behavior in a new mouse model of chorea-acanthocytosis

Chorea-acanthocytosis (ChAc) is an inherited neurodegenerative movement disorder caused by VPS13A gene mutations leading to the absence of protein expression. The striatum is the most affected brain region in ChAc patients. However, the study of the VPS13A function in the brain has been poorly addressed. Here we generated a VPS13A knockdown (KD) model and aimed to elucidate the contribution of VPS13A to synaptic plasticity and neuronal communication in the corticostriatal circuit. First, we infected primary cortical neurons with miR30-shRNA against VPS13A and analyzed its effects on neuronal plasticity. VPS13A-KD neurons showed a higher degree of branching than controls, accompanied by decreased BDNF and PSD-95 levels, indicative of synaptic alterations. We then injected AAV-KD bilaterally in the frontal cortex and two different regions of the striatum of mice and analyzed the effects of VPS13A-KD on animal behavior and synaptic plasticity. VPS13A-KD mice showed modification of the locomotor behavior pattern, with increased exploratory behavior and hyperlocomotion. Corticostriatal dysfunction in VPS13A-KD mice was evidenced by impaired striatal long-term depression (LTD) after stimulation of cortical afferents, which was partially recovered by BDNF administration. VPS13A-KD did not lead to neuronal loss in the cortex or the striatum but induced a decrease in the neuronal release of CX3CL1 and triggered a microglial reaction, especially in the striatum. Notably, CX3CL1 administration partially restored the impaired corticostriatal LTD in VPS13A-KD mice. Our results unveil the involvement of VPS13A in neuronal connectivity modifying BDNF and CX3CL1 release. Moreover, the involvement of VPS13A in synaptic plasticity and motor behavior provides key information to further understand not only ChAc pathophysiology but also other neurological disorders.

Gradients of striatal function in antipsychotic-free first-episode psychosis and schizotypy

Both psychotic illness and subclinical psychosis-like experiences (PLEs) have been associated with cortico-striatal dysfunction. This work has largely relied on a discrete parcellation of the striatum into distinct functional areas, but recent evidence suggests that the striatum comprises multiple overlapping and smoothly varying gradients (i.e., modes) of functional organization. Here, we investigated two of these functional connectivity modes, previously associated with variations in the topographic patterning of cortico-striatal connectivity (first-order gradient), and dopaminergic innervation of the striatum (second-order gradient), and assessed continuities in striatal function from subclinical to clinical domains. We applied connectopic mapping to resting-state fMRI data to obtain the first-order and second-order striatal connectivity modes in two distinct samples: (1) 56 antipsychotic-free patients (26 females) with first-episode psychosis (FEP) and 27 healthy controls (17 females); and (2) a community-based cohort of 377 healthy individuals (213 females) comprehensively assessed for subclinical PLEs and schizotypy. The first-order “cortico-striatal” and second-order “dopaminergic” connectivity gradients were significantly different in FEP patients compared to controls bilaterally. In the independent sample of healthy individuals, variations in the left first-order “cortico-striatal” connectivity gradient were associated with inter-individual differences in a factor capturing general schizotypy and PLE severity. The presumed cortico-striatal connectivity gradient was implicated in both subclinical and clinical cohorts, suggesting that variations in its organization may represent a neurobiological trait marker across the psychosis continuum. Disruption of the presumed dopaminergic gradient was only noticeable in patients, suggesting that neurotransmitter dysfunction may be more apparent to clinical illness.

Distinct reinforcement learning profiles distinguish between language and attentional neurodevelopmental disorders

BackgroundTheoretical models posit abnormalities in cortico-striatal pathways in two of the most common neurodevelopmental disorders (Developmental dyslexia, DD, and Attention deficit hyperactive disorder, ADHD), but it is still unclear what distinct cortico-striatal dysfunction might distinguish language disorders from others that exhibit very different symptomatology. Although impairments in tasks that depend on the cortico-striatal network, including reinforcement learning (RL), have been implicated in both disorders, there has been little attempt to dissociate between different types of RL or to compare learning processes in these two types of disorders. The present study builds upon prior research indicating the existence of two learning manifestations of RL and evaluates whether these processes can be differentiated in language and attention deficit disorders. We used a two-step RL task shown to dissociate model-based from model-free learning in human learners.ResultsOur results show that, relative to neurotypicals, DD individuals showed an impairment in model-free but not in model-based learning, whereas in ADHD the ability to use both model-free and model-based learning strategies was significantly compromised.ConclusionsThus, learning impairments in DD may be linked to a selective deficit in the ability to form action-outcome associations based on previous history, whereas in ADHD some learning deficits may be related to an incapacity to pursue rewards based on the tasks' structure. Our results indicate how different patterns of learning deficits may underlie different disorders, and how computation-minded experimental approaches can differentiate between them.

Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice

Huntington’s disease (HD) is a progressive, neurodegenerative disease caused by a CAG triplet expansion in huntingtin. Although corticostriatal dysfunction has long been implicated in HD, the determinants and pathway specificity of this pathophysiology are not fully understood. Here, using a male zQ175+/− knock-in mouse model of HD we carry out optogenetic interrogation of intratelencephalic and pyramidal tract synapses with principal striatal spiny projection neurons (SPNs). These studies reveal that the connectivity of intratelencephalic, but not pyramidal tract, neurons with direct and indirect pathway SPNs increased in early symptomatic zQ175+/− HD mice. This enhancement was attributable to reduced pre-synaptic inhibitory control of intratelencephalic terminals by striatal cholinergic interneurons. Lowering mutant huntingtin selectively in striatal cholinergic interneurons with a virally-delivered zinc finger repressor protein normalized striatal acetylcholine release and intratelencephalic functional connectivity, revealing a node in the network underlying corticostriatal pathophysiology in a HD mouse model.

A failure of sleep-dependent consolidation of visuoperceptual procedural learning in young adults with ADHD

ADHD has been associated with cortico-striatal dysfunction that may lead to procedural memory abnormalities. Sleep plays a critical role in consolidating procedural memories, and sleep problems are an integral part of the psychopathology of ADHD. This raises the possibility that altered sleep processes characterizing those with ADHD could contribute to their skill-learning impairments. On this basis, the present study tested the hypothesis that young adults with ADHD have altered sleep-dependent procedural memory consolidation. Participants with ADHD and neurotypicals were trained on a visual discrimination task that has been shown to benefit from sleep. Half of the participants were tested after a 12-h break that included nocturnal sleep (sleep condition), whereas the other half were tested after a 12-h daytime break that did not include sleep (wakefulness condition) to assess the specific contribution of sleep to improvement in task performance. Despite having a similar degree of initial learning, participants with ADHD did not improve in the visual discrimination task following a sleep interval compared to neurotypicals, while they were on par with neurotypicals during the wakefulness condition. These findings represent the first demonstration of a failure in sleep-dependent consolidation of procedural learning in young adults with ADHD. Such a failure is likely to disrupt automatic control routines that are normally provided by the non-declarative memory system, thereby increasing the load on attentional resources of individuals with ADHD.

Impairments in goal-directed action and reversal learning in a proportion of individuals with psychosis

Cognitive impairment in psychosis is one of the strongest predictors of functional decline. Problems with decision-making processes, such as goal-directed action and reversal learning, can reflect cortico-striatal dysfunction. The heterogenous symptoms and neurobiology observed in those with psychosis suggests that specific cognitive phenotypes may reflect differing causative mechanisms. As such, decision-making performance could identify subgroups of individuals with more severe cortico-striatal dysfunction and help to predict their functional decline. The present work evaluated the relationship between goal-directed action, reversal learning, and symptom profiles in those with psychosis. We assessed decision-making processes in healthy controls (N = 34) and those with persistent psychosis (N = 45), subclassifying subjects based on intact/impaired goal-directed action. Compared with healthy controls (<20%), a large proportion (58%) of those with persistent psychosis displayed impaired goal-directed action, predicting poor serial reversal learning performance. Computational approaches indicated that those with impaired goal-directed action had a decreased capacity to rapidly update their prior beliefs in the face of changing contingencies. Impaired decision-making also was associated with reduced levels of grandiosity and increased problems with abstract thinking. These findings suggest that prominent decision-making deficits, indicative of cortico-striatal dysfunction, are present in a large proportion of people with persistent psychosis. Moreover, these impairments would have significant functional implications in terms of planning and abstract thinking.

Alcohol withdrawal symptoms predict corticostriatal dysfunction that is reversed by prazosin treatment in alcohol use disorder.

Chronic alcohol use increases risk of alcohol withdrawal symptoms (AW) and disrupts stress biology and resilient coping, thereby promoting excessive alcohol intake. Chronic alcohol intake and multiple alcohol detoxifications are known to impair brain medial prefrontal cortex (mPFC) and striatal functioning, regions involved in regulating stress, craving and alcohol intake. In two related studies, we examined whether AW predicts this functional brain pathology and whether Prazosin versus Placebo treatment may reverse these effects. In Study 1, patients with Alcohol Use Disorder (AUD) (N = 45) with varying AW levels at treatment entry were assessed to examine AW effects on corticostriatal responses to stress, alcohol cue and neutral visual images with functional magnetic resonance imaging (fMRI). In Study 2, 23 AUD patients entering a 12-week randomised controlled trial (RCT) of Prazosin, an alpha1 adrenergic antagonist that decreased withdrawal-related alcohol intake in laboratory animals, participated in two fMRI sessions at pretreatment and also at week 9-10 of chronic treatment (Placebo: N = 13; Prazosin: N=10) to assess Prazosin treatment effects on alcohol-related cortico-striatal dysfunction. Study 1 results indicated that higher AW predicted greater disruption in brain mPFC and striatal response to stress and alcohol cues (p < 0.001, family-wise error [FWE] correction) and also subsequently greater heavy drinking days (HDD) in early treatment (p < 0.01). In Study 2, Prazosin versus Placebo treatment reversed mPFC-striatal dysfunction (p < 0.001, FWE), which in turn predicted fewer drinking days (p < 0.01) during the 12-week treatment period. These results indicate that AW is a significant predictor of alcohol-related prefrontal-striatal dysfunction, and Prazosin treatment reversed these effects that in turn contributed to improved alcohol treatment outcomes.

Reduced Axon Calibre in the Associative Striatum of the Sapap3 Knockout Mouse.

Pathological repetitive behaviours are a common feature of various neuropsychiatric disorders, including compulsions in obsessive–compulsive disorder or tics in Gilles de la Tourette syndrome. Clinical research suggests that compulsive-like symptoms are related to associative cortico-striatal dysfunctions, and tic-like symptoms to sensorimotor cortico-striatal dysfunctions. The Sapap3 knockout mouse (Sapap3-KO), the current reference model to study such repetitive behaviours, presents both associative as well as sensorimotor cortico-striatal dysfunctions. Previous findings point to deficits in both macro-, as well as micro-circuitry, both of which can be affected by neuronal structural changes. However, to date, structural connectivity has not been analysed. Hence, in the present study, we conducted a comprehensive structural characterisation of both associative and sensorimotor striatum as well as major cortical areas connecting onto these regions. Besides a thorough immunofluorescence study on oligodendrocytes, we applied AxonDeepSeg, an open source software, to automatically segment and characterise myelin thickness and axon area. We found that axon calibre, the main contributor to changes in conduction speed, is specifically reduced in the associative striatum of the Sapap3-KO mouse; myelination per se seems unaffected in associative and sensorimotor cortico-striatal circuits.

Transcranial Magnetic Stimulation Exerts "Rejuvenation" Effects on Corticostriatal Synapses after Partial Dopamine Depletion.

In experimental models of Parkinson's disease (PD), different degrees of degeneration to the nigrostriatal pathway produce distinct profiles of synaptic alterations that depend on progressive changes in N-methyl-D-aspartate receptors (NMDAR)-mediated functions. Repetitive transcranial magnetic stimulation (rTMS) induces modifications in glutamatergic and dopaminergic systems, suggesting that it may have an impact on glutamatergic synapses modulated by dopamine neurotransmission. However, no studies have so far explored the mechanisms of rTMS effects at early stages of PD. We tested the hypothesis that in vivo application of rTMS with intermittent theta-burst stimulation (iTBS) pattern alleviates corticostriatal dysfunctions by modulating NMDAR-dependent plasticity in a rat model of early parkinsonism. Dorsolateral striatal spiny projection neurons (SPNs) activity was studied through ex vivo whole-cell patch-clamp recordings in corticostriatal slices obtained from 6-hydroxydopamine-lesioned rats, subjected to a single session (acute) of iTBS and tested for forelimb akinesia with the stepping test. Immunohistochemical analyses were performed to analyze morphological correlates of plasticity in SPNs. Acute iTBS ameliorated limb akinesia and rescued corticostriatal long-term potentiation (LTP) in SPNs of partially lesioned rats. This effect was abolished by applying a selective inhibitor of GluN2B-subunit-containing NMDAR, suggesting that iTBS treatment could be associated with an enhanced activation of specific NMDAR subunits, which are major regulators of structural plasticity during synapse development. Morphological analyses of SPNs revealed that iTBS treatment reverted dendritic spine loss inducing a prevalence of thin-elongated spines in the biocytin-filled SPNs. Taken together, our data identify that an acute iTBS treatment produces a series of plastic changes underlying striatal compensatory adaptation in the parkinsonian basal ganglia circuit. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Childhood neglect is associated with corticostriatal circuit dysfunction in bipolar disorder adults

Bipolar disorder (BD) is characterized with cognitive impairment, which may be mediated by corticostriatal dysfunction. Here we examined whether history of childhood trauma, a risk factor for BD, was linked to corticostriatal dysfunction in BD patients. Furthermore, the possible associations between childhood trauma and cognitive impairment were examined. Thirty-eight BD participants who met the DSM-IV diagnostic criteria were enrolled. Childhood trauma was identified via the Childhood Trauma Questionnaire (CTQ). Participants completed the Wisconsin Card-Sorting Test (WCST). Resting-state functional magnetic resonance imaging (rsfMRI) was performed in participants using a 3T scanner. Bilateral caudate to whole-brain functional connectivity (FC) were analyzed, and childhood trauma was entered as a regressor of interest when controlling for age. Results showed the level of physical neglect was negatively correlated with left-caudate-seed FC to the frontoparietal network, including the right supramarginal gyrus, left inferior parietal lobule, right middle frontal gyrus, and right superior parietal lobule. The level of physical neglect was also negatively correlated with WCST performance. And the left-caudate-seed FCs to the frontoparietal network were positively correlated with WCST performance. Unequivocally, the specific impacts of physical neglect on brain connectivity and executive function in the BD population merit further investigation.

Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior.

Hyperactivity in striatum is associated with compulsive behaviors in obsessive-compulsive disorder (OCD) and related illnesses, but it is unclear whether this hyperactivity is due to intrinsic striatal dysfunction or abnormalities in corticostriatal inputs. Understanding the cellular and circuit properties underlying striatal hyperactivity could help inform the optimization of targeted stimulation treatments for compulsive behavior disorders. To investigate the cellular and synaptic abnormalities that may underlie corticostriatal dysfunction relevant to OCD, we used the Sapap3 knock-out (Sapap3-KO) mouse model of compulsive behaviors, which also exhibits hyperactivity in central striatum. Ex vivo electrophysiology in double-transgenic mice was used to assess intrinsic excitability and functional synaptic input in spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in central striatum of Sapap3-KOs and wild-type (WT) littermates. While we found no differences in intrinsic excitability of SPNs or FSIs between Sapap3-KOs and WTs, excitatory drive to FSIs was significantly increased in KOs. Contrary to predictions, lateral orbitofrontal cortex-striatal synapses were not responsible for this increased drive; optogenetic stimulation revealed that lateral orbitofrontal cortex input to SPNs was reduced in KOs (∼3-fold) and unchanged in FSIs. However, secondary motor area (M2) postsynaptic responses in central striatum were significantly increased (∼6-fold) in strength and reliability in KOs relative to WTs. These results suggest that increased M2-striatal drive may contribute to both in vivo striatal hyperactivity and compulsive behaviors, and support a potential role for presupplementary/supplementary motor cortical regions in the pathology and treatment of compulsive behavior disorders.SIGNIFICANCE STATEMENT These findings highlight an unexpected contribution of M2 projections to striatal dysfunction in the Sapap3-KO obsessive-compulsive disorder (OCD)-relevant mouse model, with M2 inputs strengthened by at least sixfold onto both spiny projection neurons and fast-spiking interneurons in central striatum. Because M2 is thought to be homologous to presupplementary/supplementary motor areas (pre-SMA/SMA) in humans, regions important for movement preparation and behavioral sequencing, these data are consistent with a model in which increased drive from M2 leads to excessive selection of sequenced motor patterns. Together with observations of hyperactivity in pre-SMA/SMA in both OCD and Tourette syndrome, and evidence that pre-SMA is a potential target for repetitive transcranial magnetic stimulation treatment in OCD, these results support further dissection of the role of M2 in compulsivity.

Motivational Impairment is Accompanied by Corticoaccumbal Dysfunction in the BACHD-Tg5 Rat Model of Huntington's Disease.

Neuropsychiatric symptoms, such as avolition, apathy, and anhedonia, precede the onset of debilitating motor symptoms in Huntington's disease (HD), and their development may give insight into early disease progression and treatment. However, the neuronal and circuit mechanisms of premanifest HD pathophysiology are not well-understood. Here, using a transgenic rat model expressing the full-length human mutant HD gene, we find early and profound deficits in reward motivation in the absence of gross motor abnormalities. These deficits are accompanied by significant and progressive dysfunction in corticostriatal processing and communication among brain areas critical for reward-driven behavior. Together, our results define early corticostriatal dysfunction as a possible pathogenic contributor to psychiatric disturbances and may help identify potential pharmacotherapeutic targets for the treatment of HD.

Control of Huntington’s Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2

Alteration of corticostriatal glutamatergic function is an early pathophysiological change associated with Huntington's disease (HD). The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here, we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant Huntingtin protein (mHTT). Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes that present additional targets for normalization of corticostriatal dysfunction in HD.

Effects of levodopa on corticostriatal circuits supporting working memory in Parkinson's disease

Working memory dysfunction is common in Parkinson's disease, even in its early stages, but its neural basis is debated. Working memory performance likely reflects a balance between corticostriatal dysfunction and compensatory mechanisms. We tested this hypothesis by examining working memory performance with a letter n-back task in 19 patients with mild-moderate Parkinson's disease and 20 demographically matched healthy controls. Parkinson's disease patients were tested after an overnight washout of their usual dopamine replacement therapy, and again after a standard dose of levodopa. FMRI was used to assess task-related activation and resting state functional connectivity; changes in BOLD signal were related to performance to disentangle pathological and compensatory processes. Parkinson's disease patients off dopamine replacement therapy displayed significantly reduced spatial extent of task-related activation in left prefrontal and bilateral parietal cortex, and poorer working memory performance, compared to controls. Amongst the Parkinson's disease patients off dopamine replacement therapy, relatively better performance was associated with greater activation of right dorsolateral prefrontal cortex compared to controls, consistent with compensatory right hemisphere recruitment. Administration of levodopa remediated the working memory deficit in the Parkinson's disease group, and resulted in a different pattern of performance-correlated activity, with a shift to greater left ventrolateral prefrontal cortex activation in patients on, compared to off dopamine replacement therapy. Levodopa also significantly increased resting-state functional connectivity between caudate and right parietal cortex (within the right fronto-parietal attentional network). The strength of this connectivity contributed to better performance in patients and controls, suggesting a general compensatory mechanism. These findings argue that Parkinson's disease patients can recruit additional neural resources, here, the right fronto-parietal network, to optimize working memory performance despite impaired corticostriatal function. Levodopa seems to both boost engagement of a task-specific prefrontal region, and strengthen a putative compensatory caudate-cortical network to support this executive function.

Cortico-Striatal-Thalamic Loop Circuits of the Orbitofrontal Cortex: Promising Therapeutic Targets in Psychiatric Illness.

Corticostriatal circuits through the orbitofrontal cortex (OFC) play key roles in complex human behaviors such as evaluation, affect regulation and reward-based decision-making. Importantly, the medial and lateral OFC (mOFC and lOFC) circuits have functionally and anatomically distinct connectivity profiles which differentially contribute to the various aspects of goal-directed behavior. OFC corticostriatal circuits have been consistently implicated across a wide range of psychiatric disorders, including major depressive disorder (MDD), obsessive compulsive disorder (OCD), and substance use disorders (SUDs). Furthermore, psychiatric disorders related to OFC corticostriatal dysfunction can be addressed via conventional and novel neurostimulatory techniques, including deep brain stimulation (DBS), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). Such techniques elicit changes in OFC corticostriatal activity, resulting in changes in clinical symptomatology. Here we review the available literature regarding how disturbances in mOFC and lOFC corticostriatal functioning may lead to psychiatric symptomatology in the aforementioned disorders, and how psychiatric treatments may exert their therapeutic effect by rectifying abnormal OFC corticostriatal activity. First, we review the role of OFC corticostriatal circuits in reward-guided learning, decision-making, affect regulation and reappraisal. Second, we discuss the role of OFC corticostriatal circuit dysfunction across a wide range of psychiatric disorders. Third, we review available evidence that the therapeutic mechanisms of various neuromodulation techniques may directly involve rectifying abnormal activity in mOFC and lOFC corticostriatal circuits. Finally, we examine the potential of future applications of therapeutic brain stimulation targeted at OFC circuitry; specifically, the role of OFC brain stimulation in the growing field of individually-tailored therapies and personalized medicine in psychiatry.

Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice

Kainate receptors are members of the glutamate receptor family that regulate synaptic function in the brain. They modulate synaptic transmission and the excitability of neurons; however, their contributions to neural circuits that underlie behavior are unclear. To understand the net impact of kainate receptor signaling, we generated knockout mice in which all five kainate receptor subunits were ablated (5ko). These mice displayed compulsive and perseverativebehaviors, including over-grooming, as well as motor problems, indicative of alterations in striatal circuits. There were deficits in corticostriatal input to spiny projection neurons (SPNs) in the dorsal striatum and correlated reductions in spine density. The behavioral alterations were not present in mice only lacking the primary receptor subunit expressed in adult striatum (GluK2 KO), suggesting that signaling through multiple receptor types is required for proper striatal function. This demonstrates that alterations in striatal function dominate the behavioral phenotype in mice without kainate receptors.

Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder.

Obsessive compulsive disorder (OCD) is substantially heritable, but few molecular genetic risk factors have been identified. Knockout mice lacking SLIT and NTRK-Like Family, Member 5 (SLITRK5) display OCD-like phenotypes including serotonin reuptake inhibitor-sensitive pathologic grooming, and corticostriatal dysfunction. Thus, mutations that impair SLITRK5 function may contribute to the genetic risk for OCD. We re-sequenced the protein-coding sequence of the human SLITRK5 gene (SLITRK5) in three hundred and seventy seven OCD subjects and compared rare non-synonymous mutations (RNMs) in that sample with similar mutations in the 1000 Genomes database. We also performed in silico assessments and in vitro functional synaptogenesis assays on the Slitrk5 mutations identified. We identified four RNM’s among these OCD subjects. There were no significant differences in the prevalence or in silico effects of rare non-synonymous mutations in the OCD sample versus controls. Direct functional testing of recombinant SLITRK5 proteins found that all mutations identified in OCD subjects impaired synaptogenic activity whereas none of the pseudo-matched mutations identified in 1000 Genomes controls had significant effects on SLITRK5 function (Fisher’s exact test P = 0.028). These results demonstrate that rare functional mutations in SLITRK5 contribute to the genetic risk for OCD in human populations. They also highlight the importance of biological characterization of allelic effects in understanding genotype-phenotype relationships as there were no statistical differences in overall prevalence or bioinformatically predicted effects of OCD case versus control mutations. Finally, these results converge with others to highlight the role of aberrant synaptic function in corticostriatal neurons in the pathophysiology of OCD.

Aetiopathological mechanisms of negative symptoms in schizophrenia

Summary Background: Negative symptoms represent core features of schizophrenia and have an unfavorable impact on the disease outcome. Unfortunately, their aetiopathology has not been elucidated yet and the effectiveness of available treatments is not satisfactory. Aims: This review aims to provide a critical overview of research findings concerning negative symptom aetiopathology, highlighting limitations and future perspectives. Results: Enduring and transient negative symptoms, as well as motivation-related and expression-related domains of negative symptoms, have different risk factors and clinical correlates, and are associated to distinct brain abnormalities. Enduring negative symptoms seem to be related to subtle, pervasive deviations in neurodevelopmental trajectories. Expression deficit, as compared with avolition, shows a stronger association with neurological soft signs, cognitive impairment and diffuse disconnectivity. Avolition/apathy is a multifaceted construct probably related to deficits of reward and action valuation and instrumental learning, subtended by cortico-striatal dysfunctions. Conclusions: Research findings support the heterogeneity of negative symptoms and are likely to pave the way for the discovery of more effective treatments.

P75NTR in Huntington's disease: beyond the basal ganglia

Huntington's disease (HD) is a fatal neurodegenerative disorder with a characteristic phenotype including chorea and dystonia, uncoordinated fine movements, cognitive decline and psychiatric disturbances. Even though the clinical diagnosis of HD relies on the manifestation of motor abnormalities, the associated memory impairments have been growing in prominence. Indeed, cognitive deficits are evident along all the disease process even in the prodrome before any motor diagnosis is given. These clinical signs have been mainly attributed to corticostriatal dysfunction being deficits of neurotrophic support, caused by either reduced levels of brain-derived neurotrophic factor (BDNF) [1] or decreased TrkB and aberrant p75NTR signalling [2, 3], one of the major pathogenic mechanism involved. However, in recent years has emerged the idea that cognitive decline in HD is likely a reflection of a widespread brain circuitry defect rather than a basal ganglia dysfunction per se. In this regard, in our recent studies we shed new light on the contribution of the hippocampal circuitry to synaptic and memory decline in HD. We demonstrated hippocampal dysfunction in a precise genetic HD mouse model that expresses endogenous levels of mutant huntingtin, HdhQ7/Q111 mice, manifested as alterations in spatial, recognition and associative memories. To get insight into the molecular mechanisms underlying such defects, we focused on p75NTR since growing evidence indicate that p75NTR plays an antagonistic role in synaptic plasticity. We demonstrated up-regulation of p75NTR in the hippocampus of distinct HD mouse models and in human brain without evident changes in the cortex, which extends our previous data showing increased p75NTR expression in the HD striatum [4]. In agreement with a critical role of aberrant p75NTR expression in hippocampal dysfunction we found preserved spatial, recognition and associative memories in new double-mutant mice expressing mutant huntingtin but “physiological” levels of p75NTR levels (HdhQ7/Q111:p75+/−mice). How aberrant p75NTR levels may mediate synaptic and memory deficits in HD is an intriguing question. On one hand, our results indicated that p75NTR directly or indirectly regulate the expression of different synaptic-related proteins previously implicated in HD synaptic and/or cognitive deficits, such as CBP, CamKII, GluA1 or BDNF since memory improvements in double mutant HdhQ7/Q111:p75+/−mice correlated with a recovery of the expression and/or phosphorylation of these molecules. On the other, the loss of dendritic spines in CA1 pyramidal neurons exhibited by HdhQ7/Q111 mutant mice was also prevented by normalization of p75NTR levels. Altogether, these data suggest that synaptic and memory deficits in HD could be related with a reduction in proteins involved in synaptic function and in the number and complexity of hippocampal dendritic spines in agreement with a role of p75NTR as a negative regulator of dendritic spine dynamics and synaptic activity. We further built on work showing that p75NTRcontributes to synaptic dysfunction and memory decline in HD by deregulation of RhoA activity, a small GTPase with complex effects on spines and thereby in synaptic plasticity [5]. Interestingly, such increase was reversed in double mutant HdhQ7/Q111:p75+/−mice suggesting a direct link between aberrant p75NTR activity, dendritic spine loss and aberrant RhoA activity. In agreement with our findings Plotkin and colleagues [3] have demonstrated that plasticity in indirect pathway spiny projection neurons (iSPNs) from BACHD mutant mice can be rescued by inhibition of the p75NTR-RhoA signalling suggesting that early corticostriatal dysfunction in HD could also be attributable to a correctable defect in BDNF signalling. Altogether, this evidence strongly suggests that, in the early stages of the disease, p75NTR antagonism should be considered an effective therapeutic strategy for restoring BDNF neuroprotective and synaptic functions. However, remains to be investigated whether therapeutic approaches targeting p75NTR inhibition should also integrate TrkB activation to produce the most favourable benefits on motor and cognitive impairments. Moreover, we have recently demonstrated that fingolimod, a compound used as an immunomodulator in Multiple Sclerosis patients, restores hippocampal synaptic plasticity and improves memory function in a mouse model of Huntington disease acting through down-regulation of TNFα and p75NTR [6]. These last evidence open the question whether p75NTR dysregulation is triggered by neuroinflammation at very early stages and whether modulation of the inflammatory response of microglia and astroglia in HD may contribute to antagonize the deleterious effects of aberrant p75NTR induced RhoA activity in synaptic plasticity. So far, our studies strongly implicates p75NTR-RhoA hippocampal dysfunction on cognitive decline in HD stressing the need to explore therapeutic strategies that target the identified pathways, not only in the striatum but also in other brain areas besides the basal ganglia which has been underestimated and are strongly involved in HD cognitive pathology

Frequency-Dependent Corticostriatal Disinhibition Resulting from Chronic Dopamine Depletion: Role of Local Striatal cGMP and GABA-AR Signaling.

The onset of motor deficits in parkinsonism is thought to result from dopamine (DA) loss-induced corticostriatal disruption and the development of excessive cortico-basal ganglia synchronization. To gain insights into the mechanisms underlying such corticostriatal dysfunction, we conducted local field potential (LFP) recordings in rats and measured how striatal manipulations of DA, cyclic guanosine monophosphate (cGMP), and gamma-aminobutyric acid- A receptor (GABA-AR) signaling impact corticostriatal transmission at specific oscillatory frequencies. Results indicate that the degree of 6-hydroxydopamine-induced DA lesion and subsequent changes in striatal DA, cGMP, and GABA-AR signaling contribute to impair LFP suppression such that the DA-depleted striatum becomes more permissive to cortically driven oscillations at 10-20 Hz, and to a lesser extent, at 40 Hz. Notably, the corticostriatal dysfunction at 40 Hz emerged only when the degree of chronic DA lesion surpassed 90%, which coincides with the appearance of severe forelimb stepping deficits. Collectively, these results indicate that several mechanisms contribute to suppress LFP within the 10-20 Hz range, yet a critical level of striatal GABAergic activity is required for sustaining corticostriatal inhibition at 40 Hz. Both the degree and chronicity of DA lesion are major contributing factors to the severity of motor and striatal GABAergic deficits that could only be reversed by strengthening local GABA-AR function.