Restoration of axon initial segment plasticity via chemogenetic activation rescues autism-related behaviors

Abstract Autism spectrum disorder (ASD) presents a major clinical challenge, necessitating the identification of novel therapeutic targets rooted in its underlying pathophysiology. The axon initial segment (AIS) is the critical site for action potential initiation and a hub for homeostatic plasticity; however, its involvement in ASD remains poorly defined. Herein, we report significant structural and functional deficits in the AIS within a clinically relevant ASD mouse model harboring a 15q11-13 duplication ( 15q dup ). We observed that pyramidal neurons in the medial prefrontal cortex (mPFC) exhibited shortened AIS, resulting in reduced neuronal excitability and impaired plasticity. Importantly, these abnormalities were specific to long-range circuits, including the mPFC–dorsal raphe nucleus (DRN) pathway, which is critical for social behavior. We employed a circuit-specific chemogenetic strategy that activates these mPFC–DRN projection neurons to test the reversibility of this phenotype. Remarkably, this targeted intervention normalized AIS structure and rescued core ASD-like behaviors, including social interaction deficits and repetitive behaviors. These results demonstrated that AIS alterations in this ASD model represent a reversible form of maladaptive plasticity, rather than permanent neuropathology. Our study highlights circuit-specific AIS modulation as a promising novel avenue for therapeutic interventions aimed at correcting fundamental neuronal excitability deficits in ASD.