Herman Wolosker, M.D., Ph.D.

Research

The NMDA type of glutamate receptors (NMDARs) are key receptors in the mammalian nervous system, and play major roles in several physiological processes that include neurotransmission, synaptic plasticity, learning, and memory. Unlike other neurotransmitter receptors that are which are activated by individual neurotransmitters, activation of NMDARs requires the binding of a coagonist (D-serine or glycine) in addition to glutamate. NMDARs also play a major role in neurodegeneration, and their excessive activation contributes to neuronal death in several neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Although previously considered an "unnatural" amino acid, D-serine is a key regulator of NMDAR activity by acting as a physiological ligand at the coagonist site. We have previously demonstrated that endogenous D-serine is synthesized from L-serine by serine racemase (SR), a brain-enriched enzyme. Recent data from SR knockout (SR-/-) mice support the notion that D-serine is indeed a physiological endogenous co-agonist of NMDARs. SR -/- mice exhibit decreased NMDAR transmission, and impaired long-term potentiation of synaptic transmission in the hippocampus. Our laboratory is investigating several aspects of D-serine neurobiology of which one is the role of D-serine in NMDAR-elicited neurotoxicity in neurodegeneration. D-serine seems to be the dominant coagonist for NMDAR-elicited neurotoxicity, and this raises the possibility that SR inhibitors may be neuroprotective in diseases, such as stroke and other neurodegenerative diseases where NMDARs are over-stimulated.