KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia

• Published in: Molecular psychiatry Vol. 21; no. 11; pp. 1517 - 1526
• Main Authors: Carr, G V, Chen, J, Yang, F, Ren, M, Yuan, P, Tian, Q, Bebensee, A, Zhang, G Y, Du, J, Glineburg, P, Xun, R, Akhile, O, Akuma, D, Pickel, J, Barrow, J C, Papaleo, F, Weinberger, D R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2016; Nature Publishing Group
• Subjects: 631/378; Animals; Behavioral Sciences; Biological Psychology; Brain - metabolism; Brain - physiology; Brain slice preparation; Cognition; Cognition & reasoning; Cognition - physiology; Cognitive ability; Deactivation; Dendrites; Development and progression; Disease Models, Animal; ERG1 Potassium Channel - genetics; ERG1 Potassium Channel - metabolism; Firing pattern; Gene expression; Gene Expression Regulation - genetics; Genes; Genetic aspects; Genetic testing; Genotype & phenotype; Health aspects; Hippocampus; Hippocampus - physiopathology; Humans; Information processing; Kinetics; Long-term potentiation; Long-Term Potentiation - physiology; Medicine; Medicine & Public Health; Memory, Short-Term; Mental disorders; Mental health; Mental task performance; Mice; Mice, Transgenic; Models, Molecular; Neurons; Neurons - metabolism; Neurosciences; original-article; Pathology, Molecular - methods; Pharmacotherapy; Phenotypes; Potassium; Potassium channels; Prefrontal cortex; Prefrontal Cortex - physiopathology; Psychiatry; Psychological aspects; Rodents; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Sensorimotor system; Short term memory; Structure-function relationships; Transgenic animals; Transgenic mice; Transport proteins; United States > US; Baltimore Maryland
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2015.219

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.