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

• Published in: Molecular psychiatry Vol. 25; no. 1; pp. 206 - 229
• Main Authors: Ren, Ming, Hu, Zhonghua, Chen, Qiang, Jaffe, Andrew, Li, Yingbo, Sadashivaiah, Vijay, Zhu, Shujuan, Rajpurohit, Nina, Heon Shin, Joo, Xia, Wei, Jia, Yankai, Wu, Jingxian, Lang Qin, Sunny, Li, Xinjian, Zhu, Jian, Tian, Qingjun, Paredes, Daniel, Zhang, Fengyu, Wang, Kuan Hong, Mattay, Venkata S., Callicott, Joseph H., Berman, Karen F., Weinberger, Daniel R., Yang, Feng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2020; Nature Publishing Group
• Subjects: 13/106; 13/44; 13/51; 14/19; 38/89; 38/91; 42/35; 42/44; 631/378; 64/110; 692/699/476/1799; 9/30; 9/74; Animals; Behavioral Sciences; Biological Psychology; Brain; Brain - metabolism; Brain mapping; Brain slice preparation; Cognition disorders; Cognitive ability; Cognitive Dysfunction - genetics; Complement activation; Complement Activation - immunology; Complement Activation - physiology; Electrophysiological recording; ERG1 Potassium Channel - genetics; ERG1 Potassium Channel - metabolism; Female; Functional magnetic resonance imaging; Gene expression; Genetic engineering; Hippocampus; Hippocampus - metabolism; Humans; Magnetic Resonance Imaging; Male; Medicine; Medicine & Public Health; Memory; Memory Disorders - physiopathology; Memory, Short-Term - physiology; Mental disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neural networks; Neuronal Plasticity - physiology; Neurons; Neurons - metabolism; Neurosciences; Pharmacotherapy; Potassium; Potassium channels; Prefrontal cortex; Prefrontal Cortex - metabolism; Psychiatry; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Short term memory; Synapses; Synaptic plasticity; Synaptic transmission; Synaptic Transmission - physiology; Synaptogenesis; Temporal Lobe - metabolism; Transgenic mice; Canada; Maryland; China
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-019-0530-1

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.