Histamine H₂ receptor deficit in glutamatergic neurons contributes to the pathogenesis of schizophrenia

Schizophrenia is a serious mental disorder, and existing antipsychotic drugs show limited efficacy and cause unwanted side effects. The development of glutamatergic drugs for schizophrenia is currently challenging. Most functions of histamine in the brain are mediated by the histamine H₁ receptor; however, the role of the H₂ receptor (H₂R) is not quite clear, especially in schizophrenia. Here, we found that expression of H₂R in glutamatergic neurons of the frontal cortex was decreased in schizophrenia patients. Selective knockout of the H₂R gene (Hrh2) in glutamatergic neurons (CaMKIIα-Cre; Hrh2 ^fl/fl) induced schizophrenia-like phenotypes including sensorimotor gating deficits, increased susceptibility to hyperactivity, social withdrawal, anhedonia, and impaired working memory, as well as decreased firing of glutamatergic neurons in the medial prefrontal cortex (mPFC) in in vivo electrophysiological tests. Selective knockdown of H₂R in glutamatergic neurons in the mPFC but not those in the hippocampus also mimicked these schizophrenia-like phenotypes. Furthermore, electrophysiology experiments established that H₂R deficiency decreased the firing of glutamatergic neurons by enhancing the current through hyperpolarization-activated cyclic nucleotide-gated channels. In addition, either H₂R overexpression in glutamatergic neurons or H₂R agonism in the mPFC counteracted schizophrenia-like phenotypes in an MK-801-induced mouse model of schizophrenia. Taken together, our results suggest that deficit of H₂R in mPFC glutamatergic neurons may be pivotal to the pathogenesis of schizophrenia and that H₂R agonists can be regarded as potentially efficacious medications for schizophrenia therapy. The findings also provide evidence for enriching the conventional glutamate hypothesis for the pathogenesis of schizophrenia and improve the understanding of the functional role of H₂R in the brain, especially in glutamatergic neurons.