Transforming Synapses to Operate During Extreme Metabolic Dysfunction

The brain requires more energy than any other organ in the body, and failure to meet these large energy demands contributes to vast neurological disorders, including stroke, Alzheimer’s disease, ALS, and many more. Despite different root causes, the loss of energy homeostasis at synapses represents a common pathophysiological event that degrades neural performance in many of these diseases. Therefore, understanding factors that limit synaptic performance during energy failure, and how to overcome them, may provide unifying solutions that span multiple neurological issues. To address this problem, we exploit an in vivo model that can improve synaptic function during metabolic stress beyond the current ability of any other species— neural circuits in the brain of frogs. Excitatory synapses within this system typically have high energy demands and fail minutes after disrupting aerobic metabolism, much like humans and other mammals. Remarkably, we discovered that hibernation transforms synapses to operate 30-fold longer without oxygen and glucose delivery, the greatest improvement in performance during severe metabolic stress reported in the vertebrate brain. Thus, we have the unique opportunity to reverse engineer how the brain modifies synaptic energy metabolism and physiology to overcome stressors that otherwise lead to the collapse of neural circuits in disease. Based on preliminary data, we hypothesize that transforming synapses to function during dire metabolic limitations involves an integrative collection of cellular processes that: (1) permits brain glycogen to serve as a lone fuel source, (2) maintains network connectivity by strengthening synapses through metabolite signaling, and (3) constrains neuronal excitability by reducing pathological Ca2+ influx. These complementary and mechanistic hypotheses will be tested using an approach that incorporates multiple physiological techniques to measure circuit, synaptic, metabolic, and ion channel function, as well as molecular tools that include single-cell RNA sequencing, single-cell qPCR, and enzyme studies to link physiology to molecular mechanisms. The core cellular systems that limit synaptic performance during energy stress are shared across species. Therefore, this project is significant because we are uniquely positioned to build a framework that informs how to overcome metabolic constraints on neural circuits, a goal that will be needed to combat multiple neurological diseases. Project Number: 1R01NS144063-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Joseph Santin | Institution: UNIVERSITY OF MISSOURI-COLUMBIA, COLUMBIA, MO | Award Amount: $329,234 | Activity Code: R01 | Study Section: Neuronal Communications Study Section[NC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11361467