Molecular Mechanisms of Regulation of Brain D-Serine Signaling and Schizophrenia

Abstract

It is widely accepted that the N-methyl-D-asparate type glutamate receptor (NMDAR) plays a crucial role in expression of a wide variety of higher order brain functions in mammals. In agreement with this concept, antagonists for the NMDAR display schizophrenomimetic effects, suggesting that reduced transmission via the receptor may be involved in the pathophysiology of schizophrenia. Because D-serine plays a pivotal role in the control of NMDAR as its endogenous co-agonist in the central nervous system, disturbed signaling of D-serine could cause the possible hypofunction of the NMDAR in schizophrenia. However, the exact mechanisms underlying the regulation of extracellular release of D-serine await further elucidation. Recently, we have demonstrated that the inhibition of neutral amino acid transporter Asc-1, the stimulation of calcium permeable AMPA receptor and the deletion of serine racemase (SR) expressed in neurons modify the extracellular D-serine contents in the medial prefrontal cortex. Therefore, these molecules may participate in tuning of the extracellular D-serine liberation and could be suitable targets for development of new pharmacotherapies for brain disorders.