Deletion Of Histamine H₁ Receptors In Cholinergic Neurons In Mice Causes Schizophrenia-like Phenotypes

Schizophrenia is a highly intractable mental disorder, whose pathogenesis mechanisms remain unclear. Accumulating evidence suggests that histamine is involved in the pathophysiology of schizophrenia via H₁ receptor. However, its roles still remain controversial and mysterious, which may be due to different actions of H₁ receptors in different type neurons. Cholinergic neurons in basal forebrain, striatum and brainstem are involved in the regulation of attention, mood and recognition, which are closely linked to various CNS disorders such as schizophrenia. In addition, decrements in cholinergic systems have been observed in the brains with schizophrenia. As histamine H₁ receptors are highly expressed in the brain regions containing large amounts of cholinergic neurons, histamine H₁ receptors on cholinergic neurons may play a vital role in pathogenesis of schizophrenia. In this study, H₁ receptors in cholinergic neurons are selectively deleted to investigate their roles in schizophrenia.We found that the mice with selective deletion of H₁ receptors in cholinergic neurons （Chat-Cre; H₁Rloxp/loxp? cKO） do not show alteration in locomotion, but show impaired prepulse inhibition （PPI） and schizophrenia-like phenotypes with negative symptoms and cognitive impairment, including abnormal social behaviors, anhedonia, impaired novel object recognition, impaired temporal order memory and anxiety-like behaviors. Moreover, cKO mice show decreased expression of ChAT in basal forebrain （BF） rather than striatum. Further, we found that excitatory and inhibitory inputs were impaired in the medial prefrontal cortex （mPFC） of cKOmice in electrophysiology.Taken together, our data firstly suggested that selective deletion of H₁ receptors in cholinergic neurons induces impaired prepulse inhibition （PPI） and schizophrenia-like phenotypes with negative symptoms and cognitive impairment, which may be caused by cholinergic systems decrements and subsequent impairment of synaptic transmission in prefrontal cortex. It may serve as a novel therapeutic target for the treatment of schizophrenia.