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

Molecular Psychiatry volume 21, pages 1517–1526 (2016)Cite this article

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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.

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Acknowledgements

This work was funded by the Intramural Research Program of the National Institute of Mental Health to the Weinberger Lab, US National Institute of Mental Health grant R01MH101102 and the Lieber Institute for Brain Development.

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  1. G V Carr and J Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA

    G V Carr, F Yang, M Ren, P Yuan, Q Tian, R Xun, D Akuma, J C Barrow & D R Weinberger

  2. Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, USA

    J Chen, A Bebensee, G Y Zhang, J Du, P Glineburg, R Xun & O Akhile

  3. Transgenic Core Facility, National Institute of Mental Health, Bethesda, MD, USA

    J Pickel

  4. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    J C Barrow

  5. Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy

    F Papaleo

  6. Departments of Psychiatry, Neurology, Neuroscience and The McKusick-Nathan Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    D R Weinberger

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Correspondence to G V Carr or D R Weinberger.

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Competing interests

Weinberger is an inventor on an NIH-held patent ‘Schizophrenia related isoform of KCNH2 and development of antipsychotic drugs’ (US patent no. 8101380). The remaining authors declare no conflict of interest.

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Carr, G., Chen, J., Yang, F. et al. KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia. Mol Psychiatry 21, 1517–1526 (2016). https://doi.org/10.1038/mp.2015.219

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