, 2009 and Kilic et al., 2010). However, this amino acid change does not have any detectable functional consequence in the receptor ( Schiffer et al., 2000), although it could convey aberrant gene dosage and/or unequal allele expression ( Schiffer et al., 2000 and Wilson et al., 2006). Indeed, mRNAs for GluK3 and other glutamate receptors are reduced in the frontal cortex of schizophrenic subjects ( Sokolov, 1998;

but see Meador-Woodruff et al., 2001). As for other subunits, GluK3 gene expression is developmentally regulated and aberrant gene dosage during development may impact disease in adulthood ( Wilson et al., 2006). Thus, further experiments learn more using transgenic animals are warranted. Ku-0059436 in vitro A clear example of gene dosage is provided by trisomy of chromosome 21, leading to Down syndrome. Grik1, the gene coding for GluK1 subunits, is located on human chromosome 21q22.1, and genetic mapping places

Grik1 in the vicinity of genes coding for APP and super oxide dismutase (SOD1; Gregor et al., 1994). However, linkage analysis failed to detect any association with familial amyotrophic lateral sclerosis and there are no data indicating any role for GluK1 gene disequilibrium dosage in Down syndrome. Based on multiple regression analyses, it appears that the effects of anxiety and depression treatment are significantly and independently associated with the Grik4 gene ( Paddock et al., 2007). An association was also observed in female patients with markers in Grik1. Together,

these data indicate that reduced expression of Grik1, Grik4, and other genes encoding KAR subunits could be implicated in mood disorders (but see Li et al., 2008). However, the sign of this implication is clearly elusive and these linkages may be circumstantial given that causal mutations have not yet been identified L-NAME HCl through linkage or candidate gene association studies. It is becoming clear that no conclusions can be reached without more precise information of the role of these subunits in general brain physiology. However, recent studies using experimental models have started to assess how the absence of one of these genes affects behavior. The ablation of Grik4 in mice results in marked hyperactivity ( Catches et al., 2012 and Lowry et al., 2013), one of the endophenotypes of patients with bipolar disorders, which has been interpreted as if lack of GluK4 activity has an anxiolytic and antidepressive-like effect ( Catches et al., 2012). Anxiety and depression are concurrent with bipolar disorders, and these data would in principle support the hypothesis that GluK4 hyperactivity could be a hallmark of bipolar phenotypes. However, genetic data from bipolar patients seem to refute this conclusion. In a case control association study, two SNP haplotypes (rs2282586 and rs1944522) exhibited a protective effect against bipolar disorder in a diverse Scottish population ( Pickard et al., 2006).