GRIK4/KA1 protein expression in human brain and correlation with bipolar disorder risk variant status

Authors

  • Helen M. Knight,

    1. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
    2. Institute for Genetics and Molecular Medicine, University of Edinburgh, Medical Genetics, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK
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  • Robert Walker,

    1. Neuropathology Unit, University of Edinburgh, Edinburgh, UK
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  • Rachel James,

    1. Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK
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  • David J. Porteous,

    1. Institute for Genetics and Molecular Medicine, University of Edinburgh, Medical Genetics, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK
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  • Walter J. Muir,

    1. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
    2. Institute for Genetics and Molecular Medicine, University of Edinburgh, Medical Genetics, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK
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    • Deceased.

  • Douglas H.R. Blackwood,

    1. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
    2. Institute for Genetics and Molecular Medicine, University of Edinburgh, Medical Genetics, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK
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  • Benjamin S. Pickard

    Corresponding author
    1. Institute for Genetics and Molecular Medicine, University of Edinburgh, Medical Genetics, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK
    2. CeNsUS, Centre for Neuroscience, University of Strathclyde, Glasgow, UK
    • Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Hamnett Wing, 161 Cathedral Street, Glasgow G4 0RE, UK.
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  • How to Cite this Article: Knight HM, Walker R, James R, Porteous DJ, Muir WJ, Blackwood DHR, Pickard BS. 2012. GRIK4/KA1 Protein Expression in Human Brain and Correlation With Bipolar Disorder Risk Variant Status. Am J Med Genet Part B 159B:21–29.

Abstract

The kainate class of ionotropic glutamate receptors is involved in the regulation of neuronal transmission and synaptic plasticity. Previously we reported that a deletion variant within the gene GRIK4, which encodes the KA1 kainate receptor subunit, was associated with a reduced risk of bipolar disorder and increased GRIK4 mRNA abundance. Using a high resolution immunohistochemistry technique, we characterized KA1 protein localization in human brain and performed a genotype–protein expression correlation study. KA1 was expressed in specific populations of neuronal cells in the cerebellum and all layers of the frontal and parahippocampal cortices. In the hippocampus, strong KA1 expression was observed in the stratum pyramidale and stratum lucidum of CA3 and CA2, in cell processes in CA1, in the neuropil of the CA4 region, in polymorphic cells including mossy fiber neurons in the hilus, and dentate gyrus (DG) granule cells. Mean counts of KA1 positive DG granule cells, hippocampal CA3 pyramidal cells, and layer 1 of the frontal cortex were significantly increased in subjects with the deletion allele (P = 0.0005, 0.018, and 0.0058, respectively) compared to subjects homozygous for the insertion. Neuronal expression levels in all regions quantified were higher in the deletion group. These results support our hypothesis that the deletion allele affords protection against bipolar disorder through increased KA1 protein abundance in neuronal cells. Biological mechanisms which may contribute to this protective effect include KA1 involvement in adult hippocampal neurogenesis, HPA axis activation, or plasticity processes affecting neuronal circuitry. © 2011 Wiley Periodicals, Inc.

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