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

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.