The Study On Schizophrenia-like Behavior Induced By Functional Deficits Of Histamine H₁ Receptor In Endothelial Cells

OBJECTIVE:Schizophrenia is a comnon psychiatric disorder with a complex pathogenesis and multiple signaling pathways and key molecules involved.Studies have reported that the expression of histamine H1 receptor in the cortex of patients with schizophrenia is down-regulated,and the content of histamine metabolites in cerebrospinal fluid is increased.In addition,some anti-schizophrenia drugs also have an antagonistic effect on histamine H1 receptor,suggesting that histamine and its Hi receptor may be involved in the pathogenesis of schizophrenia.Histamine H1 receptor is highly expressed on vascular endothelial cells,and vascular endothelial cells play an indispensable role in regulating neural activity as an important component of the widely distributed neurovascular unit in the brain.Therefore,this experiment uses Cre/LoxP technology to selectively alter the expression of histamine H1 receptor on vascular endothelial cells,and then explore the role of histamine H i receptor in schizophrenia on vascular endothelial cells.METHODS:1)Cdh5-Cre mice were mated with Hrh1f/f mice to obtain vascular endothelial cell histamine H1 receptor-deficient mice.2)Behavioral methods were used to detect changes in the behavioral phenotype of mice after loss of histamine H1 receptor function in vascular endothelial cells.3)Electrophysiological methods were used to detect the membrane properties and synaptic transmission in the medial prefrontal cortex and hippocampal pyramidal neurons in mice.4)Immunohistochemical methods were used to detect changes in vascular structure and activation of glial cells in related brain regions.RESULTS:After specifically knocking out the histamine H1 receptor in vascular endothelial cells,this mice showed developmental disorders and could not survive to adulthood.Therefore,vascular endothelial cell histamine H1 receptor knockdown mice(Cdh5-cre;Hrhf/n)were used as experimental mice in this study.Mice which does not express the Cre gene(Hrhlf/n mice)were used as control mice.Behavioral results showed that compared with the control group,the experimental mice had less locomotion during the open field test,but their exercise capacity,anxiety and depression did not change.In addition,the experimental mice also suffered cognitive function damage.In addition,compared with the control group,the experimental mice showed a decrease in social ability,as well as the phenotype such as social apathy,accompanied by a decline in nesting ability and a lack of pleasure.Finally,prepulse inhibition experiments showed that the ability of the experimental mice to respond to external stimuli decreased.Further,through electrophysiological experiments,we found that the excitatory synaptic transmission in the prefrontal cortex and hippocampus of the experimental mice decreased,while the inhibition of synaptic transmission did not change.Moreover,we detected vascular structural destruction and activation of microglia and astrocytes in the above brain regions.CONCLUSION:Vascular endothelial cell histamine Hi receptor function-deficient mice exhibit negative symptoms of schizophrenia,which was represented by decreased exercise,social apathy,and impaired prepulse inhibition,accompanied with cognitive impairment.These phenotypes may be caused by impaired vascular structure which was resulted of impaired function of histamine H1 receptor in vascular endothelial cells,which induces activation of glial cells in related brain regions and causes abnormal synaptic transmission in the corresponding brain regions.