Inhibition of glycolysis prevents behavioural changes in mice with MK801-induced SCZ model by alleviating lactate accumulation and lactylation

Schizophrenia (SCZ) is a debilitating neuropsychiatric disorder with a complex aetiology. Cognitive symptoms and hippocampal changes have been implicated in the pathophysiology of SCZ. Changes in metabolites level and up-regulated glycolysis have been reported in previous studies, which may be related to the hippocampal dysfunction in SCZ. However, the pathological mechanism of glycolysis involved in the pathogenesis of SCZ remains unclear. Therefore, the change of glycolysis level and the involvement in SCZ need to be further studied. In our study, MK801 was used to induce an SCZ mouse model and cell model in vivo and in vitro. Western blotting was performed to evaluate the levels of glycolysis, metabolites, and lactylation in hippocampal tissue of mice with SCZ or cell models. The level of high mobility group protein 1 (HMGB1) in the medium of MK801-treated primary hippocampal neurons was examined. Apoptosis was evaluated in HMGB1-treated hippocampal neurons by flow cytometry. The glycolysis inhibitor 2-DG prevented behavioural changes in the MK801-induced SCZ mouse model. The lactate accumulation and level of lactylation were alleviated in the hippocampal tissue of MK801-treated mice. Glycolysis was enhanced, and lactate accumulated in MK-801-treated primary hippocampal neurons. In addition, the level of HMGB1 increased in the medium and induced Apoptosis in primary hippocampal neurons. Together, the data showed that glycolysis and lactylation increased in the MK801-induced SCZ model in vivo and in vitro, and this effect could be prevented by 2-DG (a glycolysis inhibitor). Glycolytic related HMGB1 upregulation may induce Apoptosis in hippocampal neurons downstream.

Glycolysis; HMGB1; Hippocampal neurons; Lactylation; Schizophrenia.