The Effects of Intrinsic Homeostatic Plasticity (IHP) on Axon Initial Segment (AIS) Remodeling in SCN2A Rats

Homeostatic plasticity stabilizes neuronal activity during development in part by adjusting intrinsic excitability in response to sensory perturbations. This mechanism is called intrinsic homeostatic plasticity (IHP), characterized by the recruitment or removal of voltage-gated sodium (Nav) or potassium (Kv) channels, changes in conductance, and modifications of the axon initial segment (AIS). The AIS is the main site of action potential initiation and is highly populated with Nav and Kv channels. However, it remains unknown whether autism spectrum disorder (ASD) associated genes may affect AIS remodeling during homeostatic perturbation. To answer this question, we used rats with a 50% loss of the SCN2A gene (SCN2A+/-), a high-confidence ASD-associated gene that encodes for Nav1.2 channels, as our animal model. Experiments were performed during the critical period (P23-P26) in the binocular visual cortex (V1b). To induce homeostatic changes, we used inhibitory DREADDS and measured AIS changes by staining for AnkG, a scaffolding protein that anchors Nav and Kv channels. Our baseline results showed that AIS structure and morphology did not change in L2/3 and L5, indicating that SCN2A haploinsufficiency does not alter AIS size or location. After activity suppression in L2/3, WT neurons showed expected compensatory structural modifications in the