Lactate phosphorylates nNOS^Ser1412 and protects against restraint stress-induced memory impairment in mice

Lactate is a potential energy source in the brain and contributes to several cognitive functions, such as learning, memory, stress resilience, and mood regulation; However, the mechanisms by which lactate contributes to stress-induced cognitive dysfunction, including the roles of nitric oxide (NO) signaling, remain unclear. We hypothesized that lactate improves cognitive dysfunction induced by acute restraint stress via neuronal NO synthase (nNOS), a major NO source in the central nervous system, and the brain-derived neurotrophic factor (BDNF) pathway. We demonstrated that lactate phosphorylates nNOS at Ser1412 and promotes the neural differentiation of Neuro2a, a mouse neuroblastoma cell line. These effects were attenuated by the monocarboxylate transporter (MCT) 1/2-selective inhibitor AR-C155858 or the nNOS-selective inhibitor 7-nitroindazole. In C57BL/6 J mice, intraperitoneal lactate administration (1 g/kg) increased nNOS phosphorylation and BDNF expression, specifically in the dorsal hippocampus, independent of AMPK and Akt activation. Under acute restraint stress conditions, prior lactate administration protected against working memory impairment as measured using the Y-maze test, and nNOS phosphorylation and BDNF expression increased in the dorsal hippocampus. However, lactate administration did not mitigate acute stress-induced anxiety-like behaviors, as assessed through the elevated plus maze test, nor did it significantly alter NO signaling in the ventral hippocampus. These findings provide evidence supporting the partial therapeutic role of elevated blood lactate concentrations, whether induced by nutrition or physiological activities, such as exercise, in mitigating cognitive dysfunction caused by acute stress.