MECHANISMS OF PROTEIN PHOSPHORYLATION AT THE AXON INITIAL SEGMENT

/ABSTRACT The axon initial segment (AIS) governs key processes of action potential generation and neuronal polarity. The functions of AIS are often perturbed in brain conditions such as autism spectrum disorder (ASD). Given its prominent placement and crucial role in dynamic neuronal signaling and communication, the AIS has long been recognized as a hotspot for protein phosphorylation. However, our knowledge of the AIS-specific phospho- regulators, i.e., kinases and phosphatases, is surprisingly lacking. Without this critical information, researchers face a significant challenge in understanding how protein phosphorylation at the AIS is regulated in health and impacted in various brain conditions. In this proposal, we will identify unique protein phosphatase subunits enriched at the AIS, and uncover the distinct molecular mechanisms that recruit them to the AIS (Aim 1). We will then dissect the molecular, electrophysiological, and behavioral phenotypes associated with these subunits by experimentally perturbing their expression (Aim 2). Finally, we will investigate how AIS-enriched kinases contribute to the regulation of AIS cytoskeletal dynamics and the neuronal activity adaptation during plasticity (Aim 3). In summary, we aim to identify new mechanisms underlying the AIS enrichment of specific factors that regulate protein phosphorylation, and elucidate their distinct contributions to AIS function, neuronal signaling, and behavior. The successful completion of this project will significantly advance the field of AIS neurobiology, and provide critical insights into the pathophysiology of brain disorders related to AIS functions. Project Number: 1R01MH140972-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Yudong Gao | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $701,256 | Activity Code: R01 | Study Section: Neuronal Communications Study Section[NC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11367624