Deletion of Fbxo25 causes excessive repetitive behavior, impaired recognition memory, reduced dendritic complexity, and aberrant protein expression in mice.

Adgrd1 deficiency reveals increased hippocampal vulnerability and selective behavioral alterations in mice

X-linked SYTL4 missense variant disrupts RAB27A-dependent vesicle trafficking and synaptic transmission in autism.

The findings implicate disrupted SYTL4-RAB27A-dependent vesicle trafficking in ASD pathogenesis and identify SYTL4 and RAB27A as previously unrecognized contributors to autism-associated synaptic deficits and behavior.

Pathogenic MAPK8IP3 variants drive distinct motor and behavioral phenotypes in humans and mice

This work establishes the first domain-resolved in vivo rodent models of NEDBA and provides a validated translational platform for mechanistic investigation and preclinical therapeutic testing.

GIT1 loss of function causes a recognizable syndromic neurodevelopmental disorder.

Evidence is provided that biallelic GIT1 variants affecting transcript processing or causing premature termination underlie a syndromic neurodevelopmental disorder and an essential role for GIT1 in development and cognitive function is established.

Altered social behavior and prefrontal dopaminergic signaling in female Dtnbp1 knockout mice.

Schizophrenia is a complex neuropsychiatric disorder associated with genetic variants of the dystrobrevin-binding protein 1 (Dtnbp1) gene. While cognitive deficits in male Dtnbp1 mutant mice are well-documented, the impact of this mutation on female subjects remains underexplored. This study investigated the behavioral and molecular effects of Dtnbp1 deficiency in male and female knockout (Dys-/-) mice, highlighting sex-specific cognitive, social, and molecular signaling impairments relevant to schizophrenia. Female Dys-/- mice exhibited an anxiolytic phenotype with intact threat memory and normal novel object recognition memory. However, they displayed profound deficits in temporal order recognition memory and multiple domains of social behavior. Conversely, male Dys-/- mice largely maintained normal social recognition. Molecular analyses revealed dysregulation of the dopaminergic system specifically in the prefrontal cortex (PFC) of female Dys-/- mice. This dysfunction was characterized by reduced mRNA expression of the dopamine receptors D1 (Drd1) and D2 (Drd2), as well as aberrant activity of canonical (DARPP-32) and noncanonical (GSK3β) signaling pathways. Collectively, these findings demonstrate 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.

Mutations in the three synapsin genes lead to profound social deficits and cortical dysfunctions.

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.