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Disruption of metabolic interactions between astrocytes and neurons, in particular of the lactate shuttle, may contribute to neurodevelopmental and psychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia. The enzyme glycine decarboxylase (GLDC), predominantly expressed in astrocytes, degrades glycine and plays a critical role in regulating NMDA receptor function and cellular metabolism. Here, we investigated whether administration of lactate would reverse schizophrenia-like phenotypes in a mouse model for psychosis with 4 copies of the Gldc gene (4cG mice). Adult male and female 4cG and wildtype mice were subjected to acute L-lactate intraperitoneal administration one hour before behavioral testing and brain collection for biochemical assays. Y-maze spontaneous alternation test, prepulse inhibition of acoustic startle test, and the three-chamber social interaction test were performed for behavioral analysis, and Western blots for protein estimations. In 4cG mice, acute lactate administration one hour before assessment rescued short-term memory deficits, acoustic startle habituation deficits, and normalized deficits in social preference behavior. Furthermore, lactate treatment restored the expression of PGC1α, a master regulator of mitochondrial biogenesis, and brain-derived neurotrophic factor (BDNF), a protein essential for synaptic plasticity. The results suggest a role for astrocytic metabolism in modulating neuronal function, and potential molecular mechanisms underlying the reversal of behavioral phenotypes. The results indicate that exogenous lactate may reverse key pathophysiological and behavioral deficits in a mouse model for schizophrenia and that lactate supplementation may be useful as a therapeutic strategy for schizophrenia and related disorders. Show less

Dingzhi Pills, a traditional Chinese medicine(TCM) formula, is frequently employed in clinical settings for treating depression, yet its treatment mechanism remains poorly understood. This study investigates the efficacy of Dingzhi Pills in mitigating depression and delineates the associated metabolic pathways. The chemical constituents of Dingzhi Pills were identified by ultra-fast liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(UFLC-Q-TOF-MS/MS). The optimal dose for treating depression in mice was determined via a mouse model of behavioral despair. Furthermore, a lipopolysaccharide(LPS)-induced depression model was established in mice and used to validate the results of pharmacological and metabolomic analyses. The results indicated that Dingzhi Pills ameliorated depression-like behaviors in mice, attenuated the LPS-induced rises in levels of inflammatory cytokines, and suppressed the activities of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), thus reducing the glutamate level. Additionally, Dingzhi Pills enhanced the expression of brain-derived neurotrophic factor(BDNF), tyrosine receptor kinase B(TrkB), mammalian target of rapamycin(mTOR), and glutamate A1(GluA1). Metabolomic profiling of the brain tissue revealed 46 unique metabolites, which served as candidate biomarkers for the antidepressant effect of Dingzhi Pills. Collectively, the data demonstrate that Dingzhi Pills alleviates depression by modulating inflammatory responses, the AMPA/BDNF/TrkB/mTOR signaling pathway, the biosynthesis of valine, leucine, and isoleucine, and the metabolism of 2-oxycarboxylic acid, providing scientific evidence for the antidepressant effect of Dingzhi Pills. Show less