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

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.

Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice

“…Conversely, increasing gene expression of Grik4 in the cortex and striatum increased anhedonic, anxiety, and depressive behaviors (Aller et al, 2015). These studies support human genetic studies that link variants in kainate receptor genes to bipolar disorder and schizophrenia (Knight et al, 2011; Pickard et al, 2008; Whalley et al, 2009). While these studies have been instructive in demonstrating a link to human disease, the dissection of the role of each of the subunits with a knockout approach has gone only part way to fully describing the roles of kainate receptors at synapses and their affects on behavior.…”

Characterization of a Novel Mutation in <b><i>SLC1A1 </i></b>Associated with Schizophrenia

“…Moreover, genome-wide association studies support the role of GRIK4 as a risk factor for schizophrenia as well as bipolar disorder [94, 95]. A deletion variant within GRIK4 that caused increases in its mRNA expression and protein abundance has been found to be associated with a reduced risk of bipolar disorder [95, 96]. Complementing these data, GRIK4-knockout mice demonstrate impairments in pre-pulse inhibition, spatial memory acquisition and recall [97].…”

Genetic ablation of the GluK4 kainate receptor subunit causes anxiolytic and antidepressant-like behavior in mice

“…Human studies of carriers of the haplotype protective against bipolar disorder have found that there are increases in mRNA and GluK4 protein associated with the deletion variant [33, 34]. There are also several studies that have found reduced KAR expression in postmortem tissue from patients with schizophrenia [42–44].…”

“…These studies identified a deletion variant in the 3′ untranslated region of GRIK4 in carriers of a haplotype that is protective against bipolar disorder [31]. In post-mortem hippocampal tissue from subjects carrying the deletion, mRNA transcripts and GluK4 protein levels are increased [33, 34]. In addition, imaging studies on healthy carriers of the protective haplotype demonstrated increased neural activity in the hippocampus during a face recognition task, demonstrating a functional effect of this genetic variation [35].…”