2454-P: Neuronal Metabolism during Synaptic Activation Is Affected by Hyperglycemia

Introduction and Objective: Diabetes is characterized by chronic hyperglycemia and damage to the central nervous system, which may lead to impaired cognitive function. Despite the linear correlation between brain and blood glucose concentrations, most neurophysiological studies use supraphysiological glucose levels (≥25 mM). Such conditions do not reflect normal neuronal function and correspond to extreme hyperglycemia. Here, we examined how mitochondrial metabolic responses to long-term potentiation (LTP), a fundamental cellular mechanism of learning and memory formation, depend on glucose availability. Methods: Primary hippocampal neurons were cultured for 14 days under either in physiological (2.5 mM) or hyperglycemic (25 mM) brain glucose conditions. On day 14, LTP was chemically induced. Cells and media were collected for metabolomic profiling using gas chromatography mass spectrometry. Results: Neuronal viability was higher under physiological glucose compared to hyperglycemia. At baseline, neurons cultured at 2.5 mM glucose exhibited reduced pyruvate, lactate, alanine and neurotransmitters while maintaining TCA cycle intermediates. Upon LTP induction, metabolic responses differed between glucose conditions, with accumulation of TCA intermediates and increased lactate release at 2.5 mM glucose, contrasted by depletion of mitochondrial metabolites and reduced lactate secretion at 25 mM glucose. Importantly, LTP induction was preserved under physiological glucose as evidenced by immunofluorescence measurements of c-Fos expression. Conclusion: Glucose availability changes neuronal metabolic responses without impairing LTP induction. These results show that studying synaptic plasticity under supraphysiological glucose conditions, such as hyperglycemia, may be misleading because neuronal metabolism differs substantially, highlighting the need for physiologically relevant models when investigating diabetes-related cognitive impairment. Disclosure N. Pudelko-Malik: None. D. Drulis-Fajdasz: None. M.M. Fydryszewski: None. S.C. Burgess: None. P. Mlynarz: None. D. Rakus: None. S. Deja: None. Funding The Kosciuszko Foundation the American Centre of Polish Culture, National Institutes of Health (K01DK133630), Polish National Science Centre (2020/37/B/NZ4/00808)