Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan.
Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.
Elife. 2024 Mar 26;12:RP89376. doi: 10.7554/eLife.89376.
Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.
乳酸是糖酵解的终产物，其水平的升高被认为是神经元兴奋过程中代谢变化的潜在替代标志物。乳酸水平的变化可导致脑 pH 值降低，这与各种神经精神障碍患者有关。我们之前的研究表明，这种改变在五种精神分裂症、双相情感障碍和自闭症的小鼠模型中很常见，这表明这些疾病之间存在共同的表型特征，而不仅仅是由于药物或濒死状态导致的假象。然而，目前对动物模型中这一现象的研究仍然有限，其在其他疾病动物模型中的普遍性尚不确定。此外，脑乳酸水平变化与特定行为异常之间的关联仍不清楚。为了解决这些差距，国际脑 pH 项目联盟在与神经精神障碍相关的遗传和其他实验操作的 2294 只动物的 109 个品系/条件中研究了脑 pH 和乳酸水平。系统分析显示，在多种抑郁症、癫痫、阿尔茨海默病和一些额外的精神分裂症模型中，脑 pH 值降低和乳酸水平升高是常见特征。虽然某些自闭症模型也表现出 pH 值降低和乳酸水平升高，但其他模型则表现出相反的模式，这可能反映了自闭症谱系内的亚群。此外，利用大规模行为测试组合，多变量交叉验证预测分析表明，工作记忆表现差主要与脑内乳酸水平升高有关。重要的是，这一关联在另一组独立的动物模型中得到了验证。总的来说，这些发现表明，改变的脑 pH 和乳酸水平，可能归因于兴奋/抑制平衡失调，可能作为以认知障碍为特征的致残性神经精神障碍的跨诊断表型特征，而不论其有益或有害的性质如何。
