50%) in the frontal cortex of schizophrenics ( Sokolov, 1998). Clearly, SNPs found in the Grik4 gene as markers of schizophrenia and bipolar disorders confirm a role for this gene as a risk factor for mood disorders. The SNPs vary with the disease, with SNPs at the center of the gene at chromosome 6q11 associated with schizophrenia and SNPs at the gene’s 3′ end associated with bipolar disorders. Clarification of aspects mentioned above is critical for envisioning therapeutic opportunities. On the one hand, data from patients

suggest that a pharmacologically mediated increase in KAR activity Epigenetic Reader Domain inhibitor might be beneficial to protect against bipolar disorders, while on the other hand, behavioral data from mice (e.g., GluK4-deficient mice) may open the door to therapeutic opportunities for antagonists (e.g., of GluK4). However, this latter approach would be detrimental to other phenotypes, such as schizophrenia. The uncertainty of interpreting behavioral data in mice must also be born in mind and, as mentioned above, reduced immobility of KO mice in the Compound C mw forced swimming test has been interpreted as antidepressant in some cases and as a sign of mania in others. A significant

decrease in GluK2 mRNA expression has been reported in schizophrenic subjects (Porter et al., 1997). Interestingly, this gene maps close to a locus of schizophrenia susceptibility on chromosome 6 (6q16.3-q21) (Bah et al., 2004), although no association between this gene and schizophrenia could be demonstrated after studying 15 SNPs evenly distributed over the entire Grik2 region, ruling out a major role of GluK2 in the pathogenesis of schizophrenia ( Shibata et al., 2002). However, several genome-wide studies STK38 have shown significant linkage between bipolar disorders and chromosome 6q21 ( McQueen et al., 2005), where Grik2 maps, and GluK2 mRNA expression is also reduced in the brain of bipolar patients ( Beneyto et al., 2007). Interestingly, Grik2 KO mice exhibit a variety of behaviors, including hyperactivity, aggressiveness, and sensitivity to psychostimulants, reproducing in mice the behavioral symptoms of mania in humans (

Shaltiel et al., 2008). However, it is not currently possible to infer whether GluK2 is involved in the pathophysiology of mania and/or susceptibility to bipolar disorders, or if it is just related to some features of their symptoms. In one of the eight genomic loci linked to nonsyndromic autosomal recessive mental retardation in a study of 78 consanguineous Iranian families, gene defects were revealed precisely in an interval on chromosome 6116.1-q21. This locus contains 25 annotated genes, including Grik2, which was screened for DNA mutations in patients with mental retardation. Only one single nonpolymorphic sequence change was detected, involving a deletion that removed exons 7 and 8 of the Grik2 gene ( Motazacker et al., 2007).