Overcoming glutamate excitotoxicity to metabolic stress

The National Institute of Neurological Disorders and Stroke, part of the Department of Health and Human Services National Institutes of Health, awarded Wake Forest University $533,623 on September 3, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

The award funds research investigating mechanisms that protect neurons from glutamate excitotoxicity during metabolic stress. The research uses avian neurons, which naturally resist the neurotoxic cascade triggered by energy depletion, as a model system to identify neuroprotection mechanisms. The project pursues three specific aims: maintaining glutamate transporter function during metabolic stress, enhancing GABAergic signaling to preserve neuronal viability, and establishing neuroprotection mechanisms in living systems. The investigator will employ patch-clamp electrophysiology, behavioral assays, and advanced microscopy to test the hypothesis. The research applies to multiple neurological conditions including stroke, respiratory arrest, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

The award supports training for two PhD students and eight undergraduates at Wake Forest University in Winston-Salem, North Carolina. The period of performance extends from September 3, 2026, through August 31, 2029.

Abstract

Neural circuits require a large amount of energy to function, making the brain highly vulnerable to metabolic failure. When ATP levels are insufficient, neurons undergo a toxic cascade characterized by glutamate accumulation in the synaptic cleft, overexcitation, dysfunction, and ultimately, cell death. These pathological events underlie several neurological conditions, from direct metabolic insults like stroke and respiratory arrest, to neurodegenerative disorders such as alzheimer's, parkinson's, ALS, among many others. Therefore, innovative approaches identifying mechanisms that prevent neuronal death and mitigate damage during energetic stress are critical for informing the development of treatments for multiple neurological disorders. My laboratory recently discovered that avian neurons completely avoid the neurotoxic cascade triggered by metabolic stress. This provides US with the opportunity to study mechanisms to evade metabolic-induced glutamate excitotoxicity in a system with exceptionally high energetic demand. Based on preliminary data, we hypothesize that this neuroprotection arises from synergistic mechanisms maintaining glutamate transporter function (aim 1) and enhancing gabaergic signaling (aim 2), which preserve neuronal function and viability in vivo (aim 3). We will test this hypothesis using an integrative approach that combines patch-clamp electrophysiology, behavioral assays, and advanced microscopy, providing hands-on training opportunities for two PHD students and eight undergraduates. This research will establish a framework for neuroprotection against metabolic glutamate excitotoxicity-critical for overcoming neuronal energetic stress across multiple brain disorders-while training the next generation of scientists and professionals.