Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of autism spectrum disorder. How SHANK3 insufficiency affects specific neural circuits and how this is related to specific symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the ventral tegmental area of mice. We identified dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors mGluR1 during the first postnatal week restored DA neuron excitatory synapse transmission and partially rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired ventral tegmental area function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy.

During corticogenesis, ventricular zone progenitors sequentially generate distinct subtypes of neurons, accounting for the diversity of neocortical cells and the circuits they form. While activity-dependent processes are critical for the differentiation and circuit assembly of postmitotic neurons, how bioelectrical processes affect nonexcitable cells, such as progenitors, remains largely unknown. Here, we reveal that, in the developing mouse neocortex, ventricular zone progenitors become more hyperpolarized as they generate successive subtypes of neurons. Experimental in vivo hyperpolarization shifted the transcriptional programs and division modes of these progenitors to a later developmental status, with precocious generation of intermediate progenitors and a forward shift in the laminar, molecular, morphological, and circuit features of their neuronal progeny. These effects occurred through inhibition of the Wnt-beta-catenin signaling pathway by hyperpolarization. Thus, during corticogenesis, bioelectric membrane properties are permissive for specific molecular pathways to coordinate the temporal progression of progenitor developmental programs and thus neocortical neuron diversity.

Synaptic NMDA-type glutamate receptors (NMDARs) play important roles in synaptic plasticity, brain development, and pathology. In the last few years, the view of NMDARs as relatively fixed components of the postsynaptic density has changed. A number of studies have now shown that both the number of receptors and their subunit compositions can be altered. During development, the synaptic NMDARs subunit composition changes, switching from predominance of NR2B-containing to NR2A-containing receptors, but little is known about the mechanisms involved in this developmental process. Here, we report that, depending on the pattern of NMDAR activation, the subunit composition of synaptic NMDARs is under extremely rapid, bidirectional control at neonatal synapses. This switching, which is at least as rapid as that seen with AMPARs, will have immediate and dramatic consequences on the integrative capacity of the synapse.

Alterations in the generation, migration and integration of different subtypes of neurons in the medial prefrontal cortex (mPFC) microcircuit could play an important role in vulnerability to schizophrenia. Using in vivo cell-type specific manipulation of pyramidal neurons (PNs) progenitors, we aim to investigate the role of the schizophrenia risk-gene DiGeorge Critical Region 2 (Dgcr2) on cortical circuit formation in the mPFC of developing mice. This report describes how Dgcr2 knock down in upper-layer PNs impacts the functional maturation of PNs and interneurons (INs) in the mPFC. First, we demonstrate that Dgcr2 knock-down disrupts laminar positioning, dendritic morphology and excitatory activity of upper-layer PNs. Interestingly, inhibitory activity is also modified in Dgcr2 knock-down PNs, suggesting a broader microcircuit alteration involving interneurons. Further analyses show that the histological maturation of parvalbumin (PV) INs is not dramatically impaired, thus implying that other INs subtypes might be at play in the reported microcircuit alteration. Overall, this study unravels how local functional deficits of the early postnatal development of the mPFC can be induced by Dgcr2 knock-down in PNs.

Mutations in the SHANK3 gene have been recognized as a genetic risk factor for Autism Spectrum Disorder (ASD), a neurodevelopmental disease characterized by social deficits and repetitive behaviors. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioral deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the Nucleus Accumbens promotes D1R-medium spiny neurons (D1R-MSNs) hyperexcitability and upregulates Transient Receptor Potential Vanilloid 4 (Trpv4) to impair social behavior. Interestingly, genetically vulnerable Shank3+/- mice, when challenged with Lipopolysaccharide to induce an acute inflammatory response, showed similar circuit and behavioral alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

Social interaction during adolescence strongly influences brain function and behavior, and the recent pandemic has emphasized the devastating effect of social distancing on mental health. While accumulating evidence has shown the importance of the reward system in encoding specific aspects of social interaction, the consequences of social isolation on the reward system and the development of social skills later in adulthood are still largely unknown. Here, we found that 1 week of social isolation during adolescence in male mice increased social interaction at the expense of social habituation and social novelty preference. Behavioral changes were accompanied by the acute hyperexcitability of putative dopamine (pDA) neurons in the ventral tegmental area and long-lasting expression of GluA2-lacking AMPARs at excitatory inputs onto pDA neurons that project to the prefrontal cortex. Social isolation-dependent behavioral deficits and changes in neural activity and synaptic plasticity were reversed by chemogenetic inhibition of oxytocin neurons in the paraventricular nucleus of the hypothalamus. These results demonstrate that social isolation in male mice has acute and long-lasting effects on social interaction and suggest that homeostatic adaptations mediate these effects within the reward circuit.

Social interaction is a complex and highly conserved behavior that safeguards survival and reproductive success. Although considerable progress has been made regarding our understanding of same-sex conspecific and non-aggressive interactions, questions regarding the precise contribution of sensory cues in social approach and their specific neurobiological correlates remain open. Here, by designing a series of experiments with diverse social and object stimuli manipulations in custom-made enclosures, we first sought to deconstruct key elements of social preference as assessed by the three-chamber task. Our results highlight the importance of social olfactory cues in approach behavior. Subsequently, we interrogated whether a social odor would activate dopaminergic neurons of the Ventral Tegmental Area in the same way as a juvenile conspecific would. Employing in vivo recordings in freely behaving mice, we observed an increase of the firing only during the transition toward the juvenile mouse and not during the transition toward the object impregnated with social odor, suggesting that these two experiences are distinct and can be differentiated at the neuronal level. Moreover, using a four-choice task, we further showed that mice prefer to explore complex social stimuli compared to isolated sensory cues. Our findings offer insights toward understanding how different sensory modalities contribute to the neurobiological basis of social behavior which can be essential when studying social deficits observed in autism-, depression-, anxiety-, or schizophrenia-related mouse models.

Mutations in the RAB39B gene cause X-linked intellectual disability (XLID), comorbid with autism spectrum disorders or early Parkinson's disease. One of the functions of the neuronal small GTPase RAB39B is to drive GluA2/GluA3 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) maturation and trafficking, determining AMPAR subunit composition at glutamatergic postsynaptic neuronal terminals. Taking advantage of the Rab39b knockout murine model, we show that a lack of RAB39B affects neuronal dendritic spine refinement, prompting a more Ca2+-permeable and excitable synaptic network, which correlates with an immature spine arrangement and behavioural and cognitive alterations in adult mice. The persistence of immature circuits is triggered by increased hypermobility of the spine, which is restored by the Ca2+-permeable AMPAR antagonist NASPM. Together, these data confirm that RAB39B controls AMPAR trafficking, which in turn plays a pivotal role in neuronal dendritic spine remodelling and that targeting Ca2+-permeable AMPARs may highlight future pharmaceutical interventions for RAB39B-associated disease conditions.

Atypical habituation and aberrant exploration of novel stimuli have been related to the severity of autism spectrum disorders (ASDs), but the underlying neuronal circuits are unknown. Here we show that chemogenetic inhibition of dopamine (DA) neurons of the ventral tegmental area (VTA) attenuates exploration toward nonfamiliar conspecifics and interferes with the reinforcing properties of nonfamiliar conspecific interaction in mice. Exploration of nonfamiliar stimuli is associated with the insertion of GluA2-lacking AMPA receptors at excitatory synapses on VTA DA neurons. These synaptic adaptations persist upon repeated exposure to social stimuli and sustain conspecific interaction. Global or VTA DA neuron-specific loss of the ASD-associated synaptic adhesion molecule neuroligin 3 alters the behavioral response toward nonfamiliar conspecifics and the reinforcing properties of conspecific interaction. These behavioral deficits are accompanied by an aberrant expression of AMPA receptors and an occlusion of synaptic plasticity. Altogether, these findings link impaired exploration of nonfamiliar conspecifics to VTA DA neuron dysfunction in mice.

Addictive drugs have in common that they cause surges in dopamine (DA) concentration in the mesolimbic reward system and elicit synaptic plasticity in DA neurons of the ventral tegmental area (VTA). Cocaine for example drives insertion of GluA2-lacking AMPA receptors (AMPARs) at glutamatergic synapes in DA neurons. However it remains elusive which molecular target of cocaine drives such AMPAR redistribution and whether other addictive drugs (morphine and nicotine) cause similar changes through their effects on the mesolimbic DA system.

Drug-evoked synaptic plasticity in the mesolimbic dopamine (DA) system reorganizes neural circuits that may lead to addictive behavior. The first cocaine exposure potentiates AMPAR excitatory postsynaptic currents (EPSCs) onto DA neurons of the VTA but reduces the amplitude of NMDAR-EPSCs. While plasticity of AMPAR transmission is expressed by insertion of calcium (Ca(2+))-permeable GluA2-lacking receptors, little is known about the expression mechanism for altered NMDAR transmission. Combining ex vivo patch-clamp recordings, mouse genetics, and subcellular Ca(2+) imaging, we observe that cocaine drives the insertion of NMDARs that are quasi-Ca(2+)-impermeable and contain GluN3A and GluN2B subunits. These GluN3A-containing NMDARs appear necessary for the expression of cocaine-evoked plasticity of AMPARs. We identify an mGluR1-dependent mechanism to remove these noncanonical NMDARs that requires Homer/Shank interaction and protein synthesis. Our data provide insight into the early cocaine-driven reorganization of glutamatergic transmission onto DA neurons and offer GluN3A-containing NMDARs as new targets in drug addiction.

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.

Parental behaviors secure the well-being of newborns and concomitantly limit negative affective states in adults, which emerge when coping with neonatal distress becomes challenging. Whether negative-affect-related neuronal circuits orchestrate parental actions is unknown. Here, we identify parental signatures in lateral habenula neurons receiving bed nucleus of stria terminalis innervation (BNSTLHb). We find that LHb neurons of virgin female mice increase their activity following pup distress vocalization and are necessary for pup-call-driven aversive behaviors. LHb activity rises during pup retrieval, a behavior worsened by LHb inactivation. Intersectional cell identification and transcriptional profiling associate BNSTLHb cells to parenting and outline a gene expression in female virgins similar to that in mothers but different from that in non-parental virgin male mice. Finally, tracking and manipulating BNSTLHb cell activity demonstrates their specificity for encoding negative affect and pup retrieval. Thus, a negative affect neural circuit processes newborn distress signals and may limit them by guiding female parenting.

Huntington's disease (HD) is a neurodegenerative disease notably characterized by progressive motor symptoms. Although the loss of medium spiny neurons (MSNs) in the striatum has been associated with motor deficits, premanifest patients already present cognitive deficiencies and show early signs of motor disabilities. Here, in a YAC128 HD mouse model, we identified impairment in motor skill consolidation at the age of 11-14 weeks. Using optogenetic stimulation, we found that excitatory synaptic transmission from motor cortex to MSNs located in the dorsolateral part of the striatum (DLS) is altered. Using single pellet reaching task, we observed that while motor skill consolidation is accompanied by a dynamic change in AMPA/NMDA ratio in wild-type (WT) mice, this form of synaptic plasticity does not occur in YAC128 mice. This study not only proposes new meaningful insight in the synaptopathic mechanisms of HD, but also highlights that deficit in motor skill consolidation-dependent synaptic plasticity at motor cortex to DLS synapses represents an early biomarker for HD.

Neocortical excitatory neurons belong to diverse cell types, which can be distinguished by their dates of birth, laminar location, connectivity, and molecular identities. During embryogenesis, apical progenitors (APs) located in the ventricular zone first give birth to deep-layer neurons, and next to superficial-layer neurons. While the overall sequential construction of neocortical layers is well-established, whether APs produce multiple neuron types at single time points of corticogenesis is unknown. To address this question, here we used FlashTag to fate-map simultaneously-born (i.e. isochronic) cohorts of AP daughter neurons at successive stages of corticogenesis. We reveal that early in corticogenesis, isochronic neurons differentiate into heterogeneous laminar, hodological and molecular cell types. Later on, instead, simultaneously-born neurons have more homogeneous fates. Using single-cell gene expression analyses, we identify an early postmitotic surge in the molecular heterogeneity of nascent neurons during which some early-born neurons initiate and partially execute late-born neuron transcriptional programs. Together, these findings suggest that as corticogenesis unfolds, mechanisms allowing increased homogeneity in neuronal output are progressively implemented, resulting in progressively more predictable neuronal identities.

Input from the sensory organs is required to pattern neurons into topographical maps during development. Dendritic complexity critically determines this patterning process; yet, how signals from the periphery act to control dendritic maturation is unclear. Here, using genetic and surgical manipulations of sensory input in mouse somatosensory thalamocortical neurons, we show that membrane excitability is a critical component of dendritic development. Using a combination of genetic approaches, we find that ablation of N-methyl-D-aspartate (NMDA) receptors during postnatal development leads to epigenetic repression of Kv1.1-type potassium channels, increased excitability, and impaired dendritic maturation. Lesions to whisker input pathways had similar effects. Overexpression of Kv1.1 was sufficient to enable dendritic maturation in the absence of sensory input. Thus, Kv1.1 acts to tune neuronal excitability and maintain it within a physiological range, allowing dendritic maturation to proceed. Together, these results reveal an input-dependent control over neuronal excitability and dendritic complexity in the development and plasticity of sensory pathways.

Haploinsufficiency of the SHANK3 gene, encoding for a scaffolding protein located in the postsynaptic density of glutamatergic synapse, has been linked to forms of autism spectrum disorders (ASDs). It has been shown that SHANK3 controls the maturation of social reward circuits in the ventral tegmental area (VTA). Whether the impairments in associative learning observed in ASD relate to SHANK3 insufficiency restricted to the reward system is still an open question. Here, we first characterize a social-conditioned place preference (CPP) paradigm based on the direct and free interaction with a juvenile and non-familiar conspecific. In both group- and single-housed C57Bl6/j late adolescence male mice, this CPP protocol promotes the formation of social-induced contextual associations that undergo extinction. Interestingly, the downregulation of Shank3 expression in the VTA altered the habituation to a non-familiar conspecific during conditioning and accelerated the extinction of social-induced conditioned responses. Thus, inspired by the literature on drugs of abuse-induced contextual learning, we propose that acquisition and extinction of CPP might be used as behavioral assays to assess social-induced contextual association and "social-seeking" dysfunctions in animal models of psychiatric disorders.

Social interactions are motivated behaviors that, in many species, facilitate learning. However, how the brain encodes the reinforcing properties of social interactions remains unclear. In this study, using in vivo recording in freely moving mice, we show that dopamine (DA) neurons of the ventral tegmental area (VTA) increase their activity during interactions with an unfamiliar conspecific and display heterogeneous responses. Using a social instrumental task, we then show that VTA DA neuron activity encodes social prediction error and drives social reinforcement learning. Thus, our findings suggest that VTA DA neurons are a neural substrate for a social learning signal that drives motivated behavior.

Inflammatory disorders of the CNS are frequently accompanied by synaptic loss, which is thought to involve phagocytic microglia and complement components. However, the mechanisms accounting for aberrant synaptic connectivity in the context of CD8+ T cell-driven neuronal damage are poorly understood. Here, we profiled the neuronal translatome in a murine model of encephalitis caused by CD8+ T cells targeting antigenic neurons. Neuronal STAT1 signaling and downstream CCL2 expression were essential for apposition of phagocytes, ensuing synaptic loss and neurological disease. Analogous observations were made in the brains of Rasmussen's encephalitis patients. In this devastating CD8+ T cell-driven autoimmune disease, neuronal STAT1 phosphorylation and CCL2 expression co-clustered with infiltrating CD8+ T cells as well as phagocytes. Taken together, our findings uncover an active role of neurons in coordinating phagocyte-mediated synaptic loss and highlight neuronal STAT1 and CCL2 as critical steps in this process that are amenable to pharmacological interventions.

Social behaviours characterize cooperative, mutualistic, aggressive or parental interactions that occur among conspecifics. Although the Ventral Tegmental Area (VTA) has been identified as a key substrate for social behaviours, the input and output pathways dedicated to specific aspects of conspecific interaction remain understudied. Here, in male mice, we investigated the activity and function of two distinct VTA inputs from superior colliculus (SC-VTA) and medial prefrontal cortex (mPFC-VTA). We observed that SC-VTA neurons display social interaction anticipatory calcium activity, which correlates with orienting responses towards an unfamiliar conspecific. In contrast, mPFC-VTA neuron population activity increases after initiation of the social contact. While protracted phasic stimulation of SC-VTA pathway promotes head/body movements and decreases social interaction, inhibition of this pathway increases social interaction. Here, we found that SC afferents mainly target a subpopulation of dorsolateral striatum (DLS)-projecting VTA dopamine (DA) neurons (VTADA-DLS). While, VTADA-DLS pathway stimulation decreases social interaction, VTADA-Nucleus Accumbens stimulation promotes it. Altogether, these data support a model by which at least two largely anatomically distinct VTA sub-circuits oppositely control distinct aspects of social behaviour.