DISSECTING STATE-DEPENDENT VISUAL THALAMOCORTICAL DYNAMICS IN A MOUSE MODEL OF ASD

Altered sensory processing is a core feature of autism spectrum disorder (ASD), yet at present our understanding of the mechanisms that contribute to these deficits is limited. In humans, mutations or deletions of the SHANK3 gene cause Phelan-McDermid syndrome, accounting for approximately one percent of ASD cases, and are strongly associated with sensory deficits. Accumulating evidence implicates thalamic dysfunction as a key contributor to these deficits, but the mechanisms linking altered thalamic function to sensory abnormalities remain poorly understood. To address this, we examine how Shank3 deficiency affects intrinsic neuronal properties and state-dependent neural dynamics along the visual pathway, with a focus on the dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (V1). Our experiments combine in vivo Neuropixels recordings in awake, behaving mice with in vitro whole-cell patch-clamp recordings in acute brain slices. Neuropixels recordings allow us to characterize the state-dependent modulation of visual responses, while patch-clamp recordings provide detailed measurements of single-cell electrophysiological properties. Our current efforts are focused on characterizing differences in cell intrinsic properties and firing modes in dLGN neurons of Shank3 knockout mice compared to wild-type controls. This project aims to advance our understanding of the neural mechanisms underlying the deficits in state-dependent visual processing reported in ASD patients.