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Mol Psychiatry. 2016 Nov;21(11):1517-1526. doi: 10.1038/mp.2015.219. Epub 2016 Feb 9.

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

Author information

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.
Transgenic Core Facility, National Institute of Mental Health, Bethesda, MD, USA.
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA.
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova, Italy.
Departments of Psychiatry, Neurology, Neuroscience and The McKusick-Nathan Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA.
Contributed equally


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.

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