A GRIK4 variant conferring protection against bipolar disorder modulates hippocampal function

Whalley, Heather C.; Pickard, Ben; McIntosh, Andrew M.; Zuliani, Riccardo; Johnstone, Eve C.; Blackwood, Douglas; Lawrie, Stephen M.; Muir, Walter; Hall, Jérémy

doi:10.1038/mp.2009.7

Cited by 16 publications

(13 citation statements)

References 7 publications

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“…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.…”

Section: Discussionsupporting

confidence: 78%

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

Marshall

Fernandes

et al. 2017

Cell Reports

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Summary Kainate receptors are members of the glutamate receptor family, that regulate synaptic function in the brain. They modulate synaptic transmission and the excitability of neurons; however, their contributions to neural circuits that underlie behavior are unclear. To understand the net impact of kainate receptor signaling, we generated knockout mice in which all five kainate receptor subunits were ablated (5ko). These mice displayed compulsive and perseverative behaviors including over grooming, as well as motor problems, indicative of alterations in striatal circuits. There were deficits in corticostriatal input to spiny projection neurons (SPNs) in the dorsal striatum and correlated reductions in spine density. The behavioral alterations were not present in mice only lacking the primary receptor subunit expressed in adult striatum (GluK2 ko), suggesting that signaling through multiple receptor types is required for proper striatal function. This demonstrates that alterations in striatal function dominate the behavioral phenotype in mice without kainate receptors.

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Section: Discussionsupporting

confidence: 78%

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

Marshall

Fernandes

et al. 2017

Cell Reports

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“…In support of this theory, we recently described a functional imaging study investigating the effect of the GRIK4 genotype on facial affective processing in healthy individuals. A significant increase in activity in the left hippocampus was associated with the deletion allele [Whalley et al, 2009]. Additional neuropsychological paradigms in conjunction with imaging may help elucidate which additional brain structures are of central importance to the GRIK4 genotype effect.…”

Section: Discussionmentioning

confidence: 96%

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

Knight

Walker

James

et al. 2011

American J of Med Genetics Pt B

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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.

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“…Moreover, this GRIK4 variant increased hippocampal activation during face processing, 41 suggesting a link between kainate receptor-mediated excitation in the hippocampus and Bipolar Disorder.…”

Section: Mutations In Kainate Receptor Subunitsmentioning

confidence: 97%

Glutamate receptor mutations in psychiatric and neurodevelopmental disorders

Soto

Altafaj

Sindreu

et al. 2014

Communicative & Integrative Biology

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Alterations in glutamatergic neurotransmission have long been associated with psychiatric and neurodevelopmental disorders (PNDD), but only recent advances in high-throughput DNA sequencing have allowed interrogation of the prevalence of mutations in glutamate receptors (GluR) among afflicted individuals. In this review we discuss recent work describing GluR mutations in the context of PNDDs. Although there are no strict relationships between receptor subunit or type and disease, some interesting preliminary conclusions have arisen. Mutations in genes coding for ionotropic glutamate receptor subunits, which are central to synaptic transmission and plasticity, are mostly associated with intellectual disability and autism spectrum disorders. In contrast, mutations of metabotropic GluRs, having a role on modulating neural transmission, are preferentially associated with psychiatric disorders. Also, the prevalence of mutations among GluRs is highly heterogeneous, suggesting a critical role of certain subunits in PNDD pathophysiology. The emerging bias between GluR subtypes and specific PNDDs may have clinical implications.

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A GRIK4 variant conferring protection against bipolar disorder modulates hippocampal function

Cited by 16 publications

References 7 publications

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

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

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

Glutamate receptor mutations in psychiatric and neurodevelopmental disorders

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