Glutamate receptor genes as candidates for schizophrenia susceptibility

The glutamatergic dysfunction hypothesis suggests that genes involved in the glutamate neurotransmitter system are candidates for schizophrenia-susceptibility genes. We have been doing systematic studies of the association of schizophrenia with each member of the glutamate receptor gene family. In this review, we summarize our results of association studies of five glutamate receptor genes, two of which are metabotropic, GRM2 and GRM3, whereas the other four are ionotropic, GRIA4, GRIK1, GRIK2 and GRIN1. Haplotype analyses using combinations of SNPs evenly distributed across the relevant genes showed significant associations of GRM3 and GRIA4 with schizophrenia. We discuss the possible involvement of glutamate receptor genes in the pathogenesis of schizophrenia, on the basis of association as well as linkage and postmortem studies previously reported. Replication of positive associations using different populations and the family-based study are necessary to confirm the results. Generation of gene-manipulated mice to represent endophenotypes of schizophrenia would be an alternative way to verify susceptibility genes. Some members of the glutamate receptor family may be promising targets for schizophrenia drugs.