OBJECTIVE Genetic variation in histamine H2 receptor(H2R)and H2R ligands are linked to schizophrenia,however little is known about how H2R contributes to pathogenesis of schizophrenia.Here,we detected a decreased expr...OBJECTIVE Genetic variation in histamine H2 receptor(H2R)and H2R ligands are linked to schizophrenia,however little is known about how H2R contributes to pathogenesis of schizophrenia.Here,we detected a decreased expression of H2R in medial prefrontal cortex(mPFC)glutamatergic neurons in schizophrenia patients.METHODS AND RESULTS Selective knockout of H2R gene(Hrh2)in glutamatergic neurons induced schizophrenia-like behaviors including sensorimotor gating deficit,increased locomotor activity,social withdrawal and anhedo⁃nia in behavior tests,as well as reduced sponta⁃neous firing of mPFC glutamatergic neurons in electrophysiological tests.Selective deletion of the Hrh2 in mPFC glutamatergic neurons but not hippocampus glutamatergic neurons also induced such schizophrenia-like behaviors.Patch-clamp electrophysiology establishes that H2R deficiency reduced the intrinsic excitability of glutamatergic neurons by up-regulation of hyperpolarization activated cyclic nucleotide-gated channels.Fur⁃thermore,either overexpression of H2R in gluta⁃matergic neurons or activation of H2R in the mPFC reversed the MK-801-induced schizophrenia-like symptoms.CONCLUSION H2R can serve as a novel drug target given that functional deficiency of this receptor in mPFC glutamatergic neurons may be crucial for the pathogenesis of schizo⁃phrenia.H2R agonists can be viewed as drug candidates for the treatment of schizophrenia.展开更多
基金National Natural Science Foundation of China(81973302)。
文摘OBJECTIVE Genetic variation in histamine H2 receptor(H2R)and H2R ligands are linked to schizophrenia,however little is known about how H2R contributes to pathogenesis of schizophrenia.Here,we detected a decreased expression of H2R in medial prefrontal cortex(mPFC)glutamatergic neurons in schizophrenia patients.METHODS AND RESULTS Selective knockout of H2R gene(Hrh2)in glutamatergic neurons induced schizophrenia-like behaviors including sensorimotor gating deficit,increased locomotor activity,social withdrawal and anhedo⁃nia in behavior tests,as well as reduced sponta⁃neous firing of mPFC glutamatergic neurons in electrophysiological tests.Selective deletion of the Hrh2 in mPFC glutamatergic neurons but not hippocampus glutamatergic neurons also induced such schizophrenia-like behaviors.Patch-clamp electrophysiology establishes that H2R deficiency reduced the intrinsic excitability of glutamatergic neurons by up-regulation of hyperpolarization activated cyclic nucleotide-gated channels.Fur⁃thermore,either overexpression of H2R in gluta⁃matergic neurons or activation of H2R in the mPFC reversed the MK-801-induced schizophrenia-like symptoms.CONCLUSION H2R can serve as a novel drug target given that functional deficiency of this receptor in mPFC glutamatergic neurons may be crucial for the pathogenesis of schizo⁃phrenia.H2R agonists can be viewed as drug candidates for the treatment of schizophrenia.
