title: KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia.
abstract: Overexpression in humans of KCNH2-3.1, which encodes a primate-specific and brain-selective isoform of the human ether-a-go-go-related potassium channel, is associated with impaired cognition, inefficient neural processing and schizophrenia. Here, we describe a new mouse model that incorporates the KCNH2-3.1 molecular phenotype. KCNH2-3.1 transgenic mice are viable and display normal sensorimotor behaviors. However, they show alterations in neuronal structure and microcircuit function in the hippocampus and prefrontal cortex, areas affected in schizophrenia. Specifically, in slice preparations from the CA1 region of the hippocampus, KCNH2-3.1 transgenic mice have fewer mature dendrites and impaired theta burst stimulation long-term potentiation. Abnormal neuronal firing patterns characteristic of the fast deactivation kinetics of the KCNH2-3.1 isoform were also observed in prefrontal cortex. Transgenic mice showed significant deficits in a hippocampal-dependent object location task and a prefrontal cortex-dependent T-maze working memory task. Interestingly, the hippocampal-dependent alterations were not present in juvenile transgenic mice, suggesting a developmental trajectory to the phenotype. Suppressing KCNH2-3.1 expression in adult mice rescues both the behavioral and physiological phenotypes. These data provide insight into the mechanism of association of KCNH2-3.1 with variation in human cognition and neuronal physiology and may explain its role in schizophrenia.
authors: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 21205, USA.
authors: Gregory V
authors: GV
authors: Carr
authors: Clinical Brain Disorders Branch; Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, 20814, USA.
authors: Jingshan
authors: J
authors: Chen
authors: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 21205, USA.
authors: Feng
authors: F
authors: Yang
authors: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 21205, USA.
authors: Ming
authors: M
authors: Ren
authors: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 21205, USA.
authors: Peixiong
authors: P
authors: Yuan
authors: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 21205, USA.
authors: Qingjun
authors: Q
authors: Tian
authors: Clinical Brain Disorders Branch; Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, 20814, USA.
authors: Audrey
authors: A
authors: Bebensee
authors: Clinical Brain Disorders Branch; Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, 20814, USA.
authors: Grace Y
authors: GY
authors: Zhang
authors: Clinical Brain Disorders Branch; Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, 20814, USA.
authors: Jing
authors: J
authors: Du
authors: Clinical Brain Disorders Branch; Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, 20814, USA.
authors: Paul
authors: P
authors: Glineburg
authors: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 21205, USA.|Clinical Brain Disorders Branch; Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, 20814, USA.
authors: Randy
authors: R
authors: Xun
authors: Clinical Brain Disorders Branch; Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, 20814, USA.
authors: Omoye
authors: O
authors: Akhile
authors: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 21205, USA.
authors: Daniel
authors: D
authors: Akuma
authors: Transgenic Core Facility, National Institute of Mental Health, Bethesda, MD, USA.
authors: James
authors: J
authors: Pickel
authors: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 21205, USA.|Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA.
authors: James C
authors: JC
authors: Barrow
authors: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova, Italy.
authors: Francesco
authors: F
authors: Papaleo
authors: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 21205, USA.|Departments of Psychiatry, Neurology, Neuroscience and The McKusick-Nathan Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA.
authors: Daniel R
authors: DR
authors: Weinberger
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D000072237:ERG1 Potassium Channel / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008570:Memory, Short-Term; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D057089:Pathology, Molecular / Q000379:methods; D017397:Prefrontal Cortex / Q000503:physiopathology; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human