Histamine H(2) receptor deficit in glutamatergic neurons contributes to the pathogenesis of schizophrenia.
Histamine H(2) receptor deficit in glutamatergic neurons contributes to the pathogenesis of schizophrenia.
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DOI：
10.1073/pnas.2207003120
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发表时间：
2023-02-28
影响因子：
11.1
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中科院分区：
文献类型：
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精神分裂症是一种严重的精神障碍，但至今仍没有令人满意的治疗方法。目前，NMDA受体介导的谷氨酸能传递缺陷被认为是精神分裂症的主要病因，但谷氨酸能药物的开发具有挑战性。在大脑中，大多数组胺功能是由H1受体介导的，H2受体（H2 R）的作用尚不清楚，特别是在精神分裂症中。我们的研究表明，H2 R的功能缺陷mPFC神经元的多巴胺能神经元可能是至关重要的精神分裂症的发病机制。mPFC神经元中的H2 R可作为精确的药物靶点，H2 R激动剂可被视为治疗的候选药物。我们的研究为丰富精神分裂症的传统谷氨酸假说提供了证据，并提高了对H2 R功能作用的理解。精神分裂症是一种严重的精神障碍，现有的抗精神病药物显示出有限的疗效，并导致不必要的副作用。精神分裂症的药物开发目前具有挑战性。组胺在脑中的大多数功能是由组胺H1受体介导的;然而，H2受体（H2 R）的作用还不十分清楚，特别是在精神分裂症中。在这里，我们发现，H2 R在额叶皮层的多巴胺能神经元的表达减少精神分裂症患者。选择性敲除海马能神经元（CaMK Ⅱ α-Cre; Hrh 2 fl/fl）中的H2 R基因（Hrh 2）诱导了精神分裂症样表型，包括感觉运动门控缺陷、对多动的易感性增加、社交退缩、快感缺乏和工作记忆受损，以及在体内电生理测试中内侧前额叶皮层（mPFC）中海马能神经元放电减少。选择性敲低mPFC中海马能神经元的H2 R，而不是海马中的H2 R，也模仿了这些精神分裂症样表型。此外，电生理学实验证实，H2 R缺乏通过增强通过超极化激活的环核苷酸门控通道的电流来减少多巴胺能神经元的放电。此外，在MK-801诱导的精神分裂症小鼠模型中，多巴胺能神经元中的H2 R过表达或mPFC中的H2 R激动可抵消精神分裂症样表型。两者合计，我们的研究结果表明，赤字的mPFC神经元H2 R可能是关键的精神分裂症的发病机制，H2 R激动剂可以被视为潜在的有效药物治疗精神分裂症。这些发现也为丰富传统的谷氨酸假说提供了证据，并提高了对H2 R在脑中，特别是在谷氨酸能神经元中功能作用的理解。
Schizophrenia is a serious mental disorder, but there are still no satisfactory treatments. Currently, NMDA receptor-mediated glutamatergic transmission deficiency is thought to be the leading factor in the etiology of schizophrenia, but development of glutamatergic drugs is challenging. In the brain, most histamine functions are mediated by the H1 receptor, and the role of the H2 receptor (H2R) is not quite clear, especially in schizophrenia. Our study demonstrates that functional deficiency of H2R in mPFC glutamatergic neurons may be crucial for the pathogenesis of schizophrenia. H2R in mPFC glutamatergic neurons may serve as a precise drug target, and H2R agonists can be viewed as candidates for the treatment. Our study provides evidence for enriching the conventional glutamate hypothesis for schizophrenia and improves the understanding of the functional role of H2R. 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.
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DOI：
10.1073/pnas.0308455101
发表时间：
2004-06-01
影响因子：
11.1
作者：
Jackson, ME;Homayoun, H;Moghaddam, B
通讯作者：
Moghaddam, B
影响因子：
10.6
作者：
Kesby, James P.;Burne, Thomas H. J.;Eyles, Darryl W.
通讯作者：
Eyles, Darryl W.
影响因子：
4.5
作者：
Egerton, Alice;Grace, Anthony A.;McGuire, Philip
通讯作者：
McGuire, Philip
影响因子：
4.5
作者：
Holley, Sandra M.;Wang, Elizabeth A.;Levine, Michael S.
通讯作者：
Levine, Michael S.
影响因子：
4.3
作者：
Kishi, T.;Iwata, N.
通讯作者：
Iwata, N.