Berberine ameliorates cognitive deficits in a schizophrenia mouse model in association with an AMPK-related immunometabolic and synaptic network

Berberine, an alkaloid from Coptis chinensis Franch., exhibits well-documented metabolic and anti-inflammatory properties. However, its therapeutic potential for schizophrenia remains largely unexplored. This study aimed to evaluate the behavioral effects of berberine in an MK-801-induced schizophrenia-like mouse model and examine associated metabolic, inflammatory, and synaptic markers. Mice received MK-801 injections followed by 25 days of oral berberine. Behavioral paradigms evaluated hyperlocomotion, affect, and cognition. Immunoassays mapped metabolic, inflammatory, neurochemical, and neurotrophic profiles across serum, hippocampus, and prefrontal cortex, alongside prefrontal synaptic proteins. Concurrently, network pharmacology was employed to contextualize global signaling networks. Berberine significantly reduced MK-801-associated hyperlocomotion and improved performance in the novel object location and recognition tests. These behavioral effects were accompanied by increased serum AMPK, GABA, and NMDAR levels and decreased serum DA, Glu, and CRP concentrations. Prefrontal analyses also showed lower NR2B, GAD67, and CRP protein levels in the berberine-treated group. Exploratory network analysis identified enriched annotations involving PI3K-Akt signaling, Th17 cell differentiation, and insulin resistance. Berberine improved selected behavioral outcomes in the MK-801 model, accompanied by changes in peripheral and central molecular markers. These findings support further preclinical investigation of berberine, while the exploratory network analysis nominates candidate pathways for subsequent experimental testing.