DTNBP1 (Dysbindin) Gene Variants: In Vivo Evidence for Effects on Hippocampal Glutamate Status

Introduction: In linkage and association studies the DTNBP1 gene has been identified as a major susceptibility gene for schizophrenia. Reduced expression of DTNBP1 was found in the hippocampus and prefrontal cortex in post mortem brains of schizophrenic patients. In vitro and animal models provide evidence that the DTNBP1 gene product dysbindin modulates the activity of the neurotransmitter glutamate in hippocampal neurons and is crucial for cell functioning and synaptogenesis. This study is the first to investigate the effects of genetic variants of DTNBP1 on the status of the glutamate system as well as neuronal integrity (N-acetylaspartate, NAA) in the hippocampus and a cortical region, the anterior cingulate cortex (ACC), in humans. Methods: In 79 healthy subjects, the association of single nucleotide polymorphisms (SNPs) rs760665 and rs909706 with absolute concentrations of glutamate and NAA in the left hippocampus and the ACC were investigated, using proton magnetic resonance spectroscopy (MRS) at 3 Tesla and a well established quantification procedure. Results: Hippocampal glutamate concentration was significantly affected by genotype of rs760665 (F=4.406, df=2,p=0.016) and rs909706 (F=3.171,df=2,p=0.048). For the concentration of NAA, a weak association with rs760665 was observed in the contrast analysis. None of the metabolites measured in the ACC showed a significant connection with either genotype. Conclusion: The results support a role of DTNBP1 gene variants in the glutamate neurotransmission system in the human brain at least in the hippocampus. This is compatible to growing evidence of a crucial role of glutamate in the pathobiology of schizophrenia. In addition, the weak association between DTNBP1 genotype and NAA is in line with a regulatory influence of dysbindin on synaptogenesis and neuronal survival.