Frame Ariel K, Sinka Jessica L, Courchesne Marc, Muhammad Rashad A, Grahovac-Nemeth Sandra, Bernards Mark A, Bartha Robert, Cumming Robert C
Department of Biology, Western University, London, ON N6A 5B7, Canada.
Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada.
iScience. 2024 Jun 21;27(7):110342. doi: 10.1016/j.isci.2024.110342. eCollection 2024 Jul 19.
The astrocyte-neuron lactate shuttle (ANLS) model posits that astrocyte-generated lactate is transported to neurons to fuel memory processes. However, neurons express high levels of lactate dehydrogenase A (LDHA), the rate-limiting enzyme of lactate production, suggesting a cognitive role for neuronally generated lactate. It was hypothesized that lactate metabolism in neurons is critical for learning and memory. Here transgenic mice were generated to conditionally induce or knockout (KO) the gene in CNS neurons of adult mice. High pattern separation memory was enhanced by neuronal induction in young females, and by neuronal KO in aged females. In older mice, induction caused cognitive deficits whereas KO caused cognitive improvements. Genotype-associated cognitive changes were often only observed in one sex or oppositely in males and females. Thus, neuronal-generated lactate has sex-specific cognitive effects, is largely indispensable at young age, and may be detrimental to learning and memory with aging.
星形胶质细胞-神经元乳酸穿梭（ANLS）模型假定，星形胶质细胞产生的乳酸被转运至神经元，为记忆过程提供能量。然而，神经元表达高水平的乳酸脱氢酶A（LDHA），即乳酸生成的限速酶，这表明神经元生成的乳酸具有认知作用。研究假设，神经元中的乳酸代谢对学习和记忆至关重要。在此，研究人员构建了转基因小鼠，以在成年小鼠的中枢神经系统神经元中条件性诱导或敲除该基因。在年轻雌性小鼠中，神经元诱导增强了高模式分离记忆，而在老年雌性小鼠中，神经元敲除增强了该记忆。在老年小鼠中，诱导导致认知缺陷，而敲除则导致认知改善。与基因型相关的认知变化通常仅在一种性别中观察到，或者在雄性和雌性中相反。因此，神经元生成的乳酸具有性别特异性的认知效应，在年轻时基本不可或缺，而随着年龄增长可能对学习和记忆有害。
