Kaempferol alleviates schizophrenia-like social and cognitive deficits through cholinergic modulation.

Conventional antipsychotics exhibit limited efficacy in treating the negative symptoms and cognitive deficits of schizophrenia. Although the dietary flavonoid kaempferol has demonstrated neuroprotective effects in various neurological disorders, its exact role and underlying mechanisms in schizophrenia remain poorly understood. This study aimed to elucidate the therapeutic role of kaempferol in schizophrenia and to investigate the underlying neural mechanisms. Behavioral deficits relevant to schizophrenia were evaluated using an MK-801-induced mouse model. Conditional knockout of the Hrh1 gene in cholinergic neurons and chemogenetic inhibition of cholinergic neurons in the nucleus of the horizontal limb of the diagonal band (HDB) were performed to further validate the observed behavioral phenotypes. Choline acetyltransferase (ChAT) expression in the HDB was assessed by immunohistochemistry, and calcium activity of HDB cholinergic neurons was monitored during behavioral tasks using fiber photometry. Kaempferol significantly ameliorated MK-801-induced deficits in sensorimotor gating, social novelty preference, and novel object recognition in mice. Conditional knockout of the Hrh1 gene in cholinergic neurons, or chemogenetic inhibition of HDB cholinergic neurons, recapitulated schizophrenia-like social and cognitive deficits, which were notably alleviated by kaempferol treatment. Furthermore, kaempferol reversed the MK-801-induced reductions in ChAT expression in the HDB and in calcium signaling dynamics of HDB cholinergic neurons associated with social and cognitive behaviors. Our findings suggest that kaempferol alleviates schizophrenia-like social and cognitive deficits by modulating cholinergic function in the HDB, highlighting its potential as a natural therapeutic agent for addressing these specific symptom domains of schizophrenia.