Jun 2026· Progress in Neuro-psychopharmacology and Biological Psychiatry· Vol 148, pp.
111810
· 0 citations· 46 references
Medicine
TL;DR
Results show that synapsin deletion is associated with a distinct profile of social and repetitive behavioral abnormalities, accompanied by a region-selective alteration in IL-mPFC firing activity, which indicates a marked deficit in sociability and social recognition in TKO mice.
Abstract
Synapsins are presynaptic proteins that regulate synaptic vesicle trafficking and neurotransmitter release. Mutations in synapsin genes are associated with epilepsy, autism spectrum disorders, and other neurodevelopmental conditions. Syn1/Syn2/Syn3 triple-knockout (TKO) mice exhibit behavioral abnormalities, but the neural mechanisms underlying these alterations remain poorly understood. Here, we characterized behavioral and electrophysiological changes in male synapsin TKO mice, focusing on social behavior and activity in prefrontal and hippocampal regions. TKO mice showed normal performance in working memory and no clear obsessive-compulsive phenotype in the T-maze and marble burying test. However, they displayed increased self-grooming and reduced exploratory rearing, indicating enhanced repetitive behavior and reduced exploratory drive. In social discrimination and social memory tests, TKO mice showed loss of social preference, impaired discrimination between familiar and unfamiliar conspecifics, reduced interaction time, and increased latency to approach. These findings indicate a marked deficit in sociability and social recognition. In vivo single-unit extracellular recordings revealed reduced and irregular firing in putative pyramidal neurons of the infralimbic medial prefrontal cortex (IL-mPFC) in TKO mice. In contrast, neuronal activity in the hippocampal CA3 region was preserved. These results show that synapsin deletion is associated with a distinct profile of social and repetitive behavioral abnormalities, accompanied by a region-selective alteration in IL-mPFC firing activity. Although behavioral alterations and cortical dysfunction may not be causally related, they suggest that IL-mPFC hypoactivity contributes to the behavioral phenotype in the absence of expression of all synapsin isoforms.
In autism spectrum disorder (ASD), children can exhibit a regressive phenotype with loss of previously acquired social and language skills in the first years of life. While the role of the GABAergic system in shaping neural circuits during development has been largely studied, its potential involvement in regressive phenotypes remains unclear. Here, we tracked the social and sensory development in Synapsin2 knockout (Syn2KO) mice, a model of ASD characterized by defective inhibitory tonic current, social deficits, and epilepsy in adulthood. We show that, after a transient early phase of impaired vocalization, young (PND 30) Syn2KO mice reached a normal social behavior. However, social behavior was regressively lost in adult (PND 120) mice, with the absence of vocalizations during the male-female interaction test associated with a drastic degeneration of the preoptic area-periaqueductal gray vocal GABAergic circuit. This deterioration began at earlier stages but was behaviorally latent. Adult Syn2KO mice also displayed sensory dysfunctions and dysregulation of the GABAergic system in the integrative posterior parietal cortex, with hyper-responsiveness of bimodal light- and sound-sensitive neurons that paralleled the social decline. Boosting tonic inhibition from birth with chronic treatment with the GABAA receptor agonist gaboxadol fully reversed social deficits, restored the integrity of vocal circuits, and the multimodal integration of sensory inputs. These results show that social regression in the Syn2KO model is a multiphase process characterized by early signs, a latent period of typical development, and a subsequent decline that can be reversed by enhancing tonic inhibition from development onward.
Lorenzo Ciano, Sebastian Sulis Sato, F. Galluzzi et al.· Molecular Psychiatry· 0 citations
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and the presence of restricted and repetitive behaviors. While ASD has a neurodevelopmental origin, it remains a lifelong condition, yet little is known about how its behavioral and neural features evolve across adulthood. Here, we investigated behavioral, synaptic, and structural alterations across the transition from early to mature adulthood in Cntnap2 knockout mice, a widely used model of ASD. Using a longitudinal behavioral approach combined with electrophysiological recordings and morphological analysis, we show that KO mice exhibit increased stereotyped and repetitive behaviors and reduced exploratory activity at both ages. However, detailed analysis of behavioral patterns revealed age-dependent differences, with early adult KO mice displaying increased behavioral persistence that later evolved into distinct patterns of behavioral sequences. These behavioral changes were associated with alterations in inhibitory synaptic transmission in the dorsolateral striatum (DLS), including changes in spontaneous inhibitory postsynaptic current (sIPSC) frequency and temporal structure. In parallel, mature adult KO mice showed structural remodeling of spiny projection neurons, characterized by increased distal dendritic arborization and age-dependent organization of dendritic spines. Together, our findings demonstrate that ASD-related alterations are not static but evolve across adulthood, revealing a multi-level reorganization of behavioral, synaptic, and structural features. These results highlight the importance of considering adulthood stages in ASD and provide new insights into the dynamic nature of the condition.
Mathieu Thabault, Cloé Fernandes-Gomes, Cloé Alcaraz et al.· Neurobiology of Disease· 0 citations
It is demonstrated that dysbindin-1 deficiency drives distinct, female-specific vulnerabilities in behavioral and molecular alterations relevant to neuropsychiatric conditions, providing insight into the sex-dependent pathophysiology of social and cognitive deficits in preclinical models of schizophrenia.
Repetitive behaviors are classically associated with autism spectrum disorder and obsessive compulsive disorder, but also occur prominently in attention-deficit/hyperactivity disorder (ADHD), yet the underlying mechanisms remain poorly understood. Our recent work identified ADHD-like behaviors in Cry1Δ11 mice, in which a mutation in a core circadian gene Cry1 produces a CRY1Δ11 protein that fails to inhibit the Gαs subunit, leading to hyperactive signaling of dopamine D1 receptor (DRD1). Although this dysregulation was initially reported in the ventral striatum, we hypothesized that similar mechanisms might be present in the dorsal striatum, a brain region critically involved in the generation of repetitive behaviors and densely populated by DRD1-expressing medium spiny neurons (MSNs). Here, we demonstrate that Cry1Δ11 mice exhibit robust repetitive behaviors, including excessive self-grooming and stereotyped rearing, which are associated with increased activity of DRD1-MSNs in the dorsolateral striatum. Chemogenetic manipulation further revealed that activation of these neurons induces excessive self-grooming, whereas their inhibition reduces such behavior, indicating bidirectional control over repetitive action. Critically, systemic administration of the DRD1 antagonist SCH23390 fully rescued both neuronal hyperactivity and behavioral abnormalities in mutant mice. Together, our findings establish a direct mechanistic link among a core circadian gene mutation, striatal dopaminergic hyperactivity, and repetitive behaviors, thereby identifying aberrant DRD1 signaling in the dorsolateral striatum as a promising target for therapeutic intervention.
Xiran Liu, Dengfeng Liu, Bingyu Long et al.· Translational Psychiatry· 0 citations
Schizophrenia (SCZ) is characterized by heterogeneous symptoms including abnormal perception, social withdrawal, and cognitive deficits. Parvalbumin-positive (PV+) interneurons are particularly vulnerable in SCZ; however, the underlying cellular basis remains unclear. In this study, we found that selective deletion of the SCZ risk gene Foxg1 in PV+ interneurons of mice recapitulated aspects of the disease phenotype, including impaired sensorimotor gating, anxiety-like behavior, social deficits, and cognitive impairments. Foxg1 deficiency caused dendritic simplification, reduced spine density, and impaired synaptic transmission in PV+ interneurons of the prelimbic cortex. Our findings indicate that FOXG1 directly drives a set of SCZ risk genes that encode synaptic receptors, adhesion molecules, scaffolding proteins, transporters, ion channels, and vesicle-trafficking proteins, thereby orchestrating PV+ interneuron synaptic function. Notably, FOXG1 activates the transcription of metabotropic glutamate receptor 3 (mGluR3), and pharmacological potentiation of mGluR3 activity alleviates behavioral deficits in Foxg1 conditional knockout mice. In conclusion, our findings identify a novel role for Foxg1 in PV+ interneurons, providing new mechanistic insights into their vulnerability to SCZ.
Pengfei Jiang, Mingzhao Su, Xue-lai Zhou et al.· Neuroscience Bulletin· 0 citations