DISConnectivity by DISC1 (Disrupted in schizophrenia 1) : Hyper- glutamatergic condition as a possible trigger of schizophrenia?

Abstract

As implied by the etymology of SZ [schizophrenia from the Greek roots skhizein (to split) and phre-n (mind)], various lines of evidence have suggested that SZ is a disease of neural disconnectivity : a failure of proper functional integration within the brain. Consistently, many of SZ-related gene products are involved in the glutamatergic transmission. We previously reported that the dysfunction of DISC, one of the strong SZ susceptible gene, caused a biphasic detrimental effect on glutamatergic synapse : DISC1 knockdown induces an enhanced glutamatergic transmission in a short term, which results in a reduced glutamatergic transmission in the end. Magnetic resonance spectroscopy (MRS) imaging of longitudinal assessment for SZ individuals have indirectly suggested the hyperglutamatergic condition in early phase of SZ in certain neuronal circuits, eventually resulting in hypoglutamatergic condition, the course of which is reminiscence of the biphasic effect of DISC1 dysfunction. The clinical study have also indicated the drastic change in disease manifestations during the course of disease. However, all drugs currently available in the field of psychiatry are designed for all stages of disease progress. In this seminar, I will overview the glutamatergic dysfunction as the pathogenesis/pathophysiology of SZ in the each stage of disease, and discuss about glutamate-related molecules as novel druggable therapeutic targets for each stage of SZ.