Excellence in Research: Role of acid-sensing ion channels in neuronal development/maturation

The function of the nervous system relies on the establishment of neuronal circuits during development. The mechanisms by which neurons adopt specific morphologies and connections remain unclear. This investigation will identify the role of a membrane protein called acid-sensing ion channel 1a, which senses brain acidity in the development and maturation of brain neurons. Through an array of methodological approaches, the study will determine the role of acid sensing in normal nervous system development. The findings from this investigation may help in devising treatments for neurodevelopmental disorders associated with dysregulation of acid-base balance. Through an integrated educational and research training program, this project will enable students at different levels, particularly those from underrepresented groups in STEM, to gain hands-on experience in diverse methodologies relevant for research in neuroscience. These experiences will better position trainees to pursue careers in STEM and contribute to broadening participation across the STEM workforce. Neuronal development and maturation are essential for the normal structure and functions of the brain. The specific signaling pathways involved in these processes, however, are not fully understood. The goal of this proposal is to test the hypothesis that acid-sensing ion channel 1a (ASIC1a), a novel proton-gated and Ca2+-permeable cation channel, plays an important role in neuronal development and maturation. Proton concentrations change locally when synaptic vesicles release their acidic contents during neurotransmission, and globally in the brain during periods of intense neural activity. For decades, the signaling role protons play in neurons remained elusive. The finding that protons can gate a distinct family of ion channels has shed new light on the mechanisms of acid signaling. ASIC1 is widely expressed in neurons of the peripheral and central nervous systems. Emerging studies have demonstrated that activation of ASIC1a plays important roles in neuronal injury associated with various neurological conditions. In contrast, the physiological functions of ASIC1a in the developing brain remain largely unclear. Using a combination of molecular biology, imaging, electrophysiology, pharmacology, proteomics, RNA-seq, in vitro and in vivo models, the proposed studies will systematically examine the role of ASIC1a in neuronal development and maturation and its underlying signaling mechanisms. Understanding the fundamental function of ASIC1a in nervous system development will advance the field of neuroscience and may also help establish novel therapeutic strategies for treating neurodevelopmental and neurodegenerative disorders. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.