Mechanisms of Social Memory Dysfunction in Mouse Models of Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder characterized by social deficits and repetitive behaviors. The disorder is often comorbid with Phelan McDermid syndrome (PMS) and Fragile X syndrome (FXS) which both result in social memory dysfunction alongside other ASD-related impairments. Currently, ASD is diagnosed based on behavioral criteria due to the lack of a consistent biomarker despite the disorder’s robust genetic component. The genes SHANK3, which encodes synaptic scaffolding proteins, and FMR1, which encodes for a nuclear export protein, are mutated in PMS and FXS, respectively. These mutations have been replicated to produce transgenic knockout (KO) mouse models of ASD. Shank3B KO and Fmr1 KO mice have enabled further investigation of the neural mechanisms causing social memory dysfunction. The hippocampal CA2 subregion, once regarded as a pass-through connective region, has since been heavily implicated in social memory regulation. Previous studies have identified abnormal extracellular matrix (ECM) structures such as perineuronal nets (PNNs) in the CA2 of Shank3B KO and Fmr1 KO mice. Additionally, manipulating the afferent signals from the supramammillary (SUM) nucleus has been shown to influence social memory. In order to characterize the developmental trajectories of social memory dysfunction related to ASD, this study conducted behavioral paradigms and histological analyses of the CA2, including of PNNs, at multiple time periods across postnatal development. Detailed analysis of behavioral data from the direct social interaction task indicated both transgenic models initially expressed social memory dysfunction at Postnatal Day (P) 14. However, Shank3B KO mice retained the impairment throughout adulthood while Fmr1 KO mice experienced a sex-dependent recovery of social memory. Despite the recovery of social memory by adulthood in Fmr1 KO mice, more subtle aspects of social interaction remained atypical. The object location task demonstrated functional non-social hippocampal dependent memory in both models. To examine whether PNN abundance and SUM afferents in the CA2 are associated with social memory dysfunction, we performed histological analyses of hippocampal sections from P14 mice. Shank3B KO mice displayed elevated PNN abundance while the opposite was observed in Fmr1 KO mice. Both transgenic models expressed increased social afferents from the SUM. When considered collectively, social memory dysfunction and CA2 abnormalities manifest differently across transgenic models of ASD, reinforcing the heterogeneity of the disorder and identifying future targets of intervention.