The Role of Serine Racemase in the Pathophysiology of Brain Disorders.

The N-methyl-d-aspartate receptor (NMDAR) is unique in requiring two agonists to bind simultaneously to open its cation channel: the neurotransmitter, glutamate, and the coagonists, glycine, or d-serine. The Snyder laboratory was the first to clone serine racemase (SR), the enzyme that synthesizes d-serine, and to localize it immunocytochemically. Our laboratory has focused on the role of d-serine in brain disorders. Silencing the expression of SR, a risk gene for schizophrenia (SCZ), in mice (SR-/-), results in a phenotype that closely resembles SCZ including: cortical atrophy, reduced dendritic spine density and complexity, downregulation of parvalbumin-positive cortical GABAergic neurons, and cognitive impairments. This pathology can be reversed by treatment of SR-/- mice with d-serine in adulthood. SR-/- mice also exhibit abnormal response toward abusable substances, such as stimulants. They show reduced behavioral sensitization to d-amphetamine, but fail to extinguish it. Place preference to cocaine is altered, and the hedonic response to it is profoundly impaired as assessed by intracranial self-stimulation. d-cycloserine, a partial agonist at the NMDAR glycine modulatory site, shows therapeutic benefit for treating pathologic anxiety in combination with behavioral therapies. Studies in vitro with cortical culture and in vivo with middle cerebral artery occlusion show that silencing SR provides substantial protection against ischemic neuronal death. Finally, the switch of SR expression from neurons to reactive astrocytes after closed head trauma accounts for the reduced in vivo neuroplasticity, electroencephalogram abnormalities, and cognitive impairments.