EARLY DEVELOPMENTAL STRUCTURAL AND FUNCTIONAL ALTERATIONS IN HIPPOCAMPAL CA1 IN <EM>SHANK3</EM> MUTANT MICE

Autism Spectrum Disorders (ASD) are a heterogeneous family of disorders characterized by impairments in social communication, repetitive behaviors and restricted interests (DSM-5). Sensory processing and cognition are commonly affected, often leading to misinterpretation of social cues and the surrounding environment. The hippocampus contributes to these functions by integrating external information with contextual cues to form cognitive maps. A mismatch between the information and local circuit dynamics could therefore result in inaccurate mental representations. Since ASD arise during development, early postnatal stages represent a sensitive period during which perturbations can alter network maturation, resulting in long-lasting circuit dysfunctions. Here, we investigated when and how hippocampal activities in CA1 deviate from its normal developmental trajectory in a mouse model of ASD, Shank3e4-9. Using calcium imaging during the two postnatal weeks, we observed increased spontaneous activity in Shank3. Under physiological conditions, synchronous activity during this period is triggered by self-generated movements (Dard et al., 2021). However, in Shank3 mice, response to movement was blunted, with a higher proportion of weakly responsive neurons and cells showing enhanced post-movement inhibition. Given the importance of spontaneous activity for circuit maturation, we assessed local circuit changes in Shank3. Immunohistochemistry revealed a reduced perisomatic inhibition provided by putative PV+ interneurons. Altogether, we show an early deficit in the representation of self-movement in this mouse model of ASD. This alteration occurs during a period thought to be the onset of the representation of the self, which may contribute to later cognitive dysfunctions, including deficits in cognitive map formation.