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KCNH2-3.1 mediates aberrant complement activation and impaired hippocampal-medial prefrontal circuitry associated with working memory deficits

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收录情况： ◇ SCIE ◇ 自然指数

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机构： [1]Lieber Institute for Brain Development, Johns Hopkins University Medical Center, Baltimore, MD, USA [2]Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA [3]Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA [4]Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA [5]McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA [6]Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA [7]Institute of Neuroscience, Chongqing Medical University, Chongqing, China [8]Department of Physiology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China [9]Unit on Neural Circuits and Adaptive Behaviours, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Bethesda, MD, USA [10]Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA [11]Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, USA [12]Section on Integrative Neuroimaging and the Clinical Brain Disorders Branch, National Institute of Mental Health, Bethesda, MD, USA [13]The Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA [14]Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China [15]Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

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Increased expression of the 3.1 isoform of the KCNH2 potassium channel has been associated with cognitive dysfunction and with schizophrenia, yet little is known about the underlying pathophysiological mechanisms. Here, by using in vivo wireless local field potential recordings during working memory processing, in vitro brain slice whole-cell patching recordings and in vivo stereotaxic hippocampal injection of AAV-encoded expression, we identified specific and delayed disruption of hippocampal-mPFC synaptic transmission and functional connectivity associated with reductions of SERPING1, CFH, and CD74 in the KCNH2-3.1 overexpression transgenic mice. The differentially expressed genes in mice are enriched in neurons and microglia, and reduced expression of these genes dysregulates the complement cascade, which has been previously linked to synaptic plasticity. We find that knockdown of these genes in primary neuronal–microglial cocultures from KCNH2-3.1 mice impairs synapse formation, and replenishing reduced CFH gene expression rescues KCNH2-3.1-induced impaired synaptogenesis. Translating to humans, we find analogous dysfunctional interactions between hippocampus and prefrontal cortex in coupling of the fMRI blood oxygen level-dependent (BOLD) signal during working memory in healthy subjects carrying alleles associated with increased KCNH2-3.1 expression in brain. Our data uncover a previously unrecognized role of the truncated KCNH2-3.1 potassium channel in mediating complement activation, which may explain its association with altered hippocampal–prefrontal connectivity and synaptic function. These results provide a potential molecular link between increased KCNH2-3.1 expression, synapse alterations, and hippocampal–prefrontal circuit abnormalities implicated in schizophrenia. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

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出版当年[2018]版：

大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区神经科学 1 区精神病学

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区神经科学 1 区精神病学

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出版当年[2017]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 PSYCHIATRY Q1 NEUROSCIENCES

最新[2023]版：

Q1 NEUROSCIENCES Q1 PSYCHIATRY Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

影响因子： 9.6 最新[2023版] 11.1 最新五年平均 11.64 出版当年[2017版] 12.439 出版当年五年平均 13.204 出版前一年[2016版] 11.973 出版后一年[2018版]

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第一作者机构： [1]Lieber Institute for Brain Development, Johns Hopkins University Medical Center, Baltimore, MD, USA

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通讯机构： [1]Lieber Institute for Brain Development, Johns Hopkins University Medical Center, Baltimore, MD, USA [5]McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA [6]Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA [11]Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, USA [13]The Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA [15]Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

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