Though the underlying causes of schizophrenia are poorly understood, there is a growing body of research implicating abnormalities in the function of NMDARs (N-methyl-D-aspartate receptors). While the exact role of NMDARs in schizophrenia is unknown, a detailed understanding of the cellular mechanisms involved in NMDAR regulation may yield insights into the pathophysiology of the illness and facilitate the development of novel therapeutic strategies.

 

NMDARs are synaptic receptors for glutamate, the most common excitatory neurotransmitter in the brain. They are composed of several subunits that play a critical role in neurodevelopment and synaptic plasticity―subtle changes in NMDAR functioning can have wide-ranging developmental and cognitive effects. John A. Gray, M.D., Ph.D., of University of California, San Francisco, with the support of a NARSAD Young Investigator Grant, set out to enhance the understanding of the mechanisms involved in synapse formation, maturation and elimination and the roles of NMDARs in mediating these processes. 

 

Dr. Gray first found that NMDARs in early development mediate a novel form of synaptic plasticity and that the subunit switch mediates a change to more mature forms of synaptic plasticity―this finding was published in Neuron in 2011. Then, using genetic manipulation techniques in mice, he went on to dissect the mechanisms involved in NMDAR targeting and trafficking. Abnormalities in these targeting and trafficking systems are thought to contribute to numerous neuropsychiatric disorders, including schizophrenia, autism and addiction. In a paper published in the March 28th edition of the journal Cell Reports, he and colleagues elucidated the mechanisms involved in the experience-mediated developmental change in NMDAR subunits at synapses.

 

Dr. Gray describes the aim of his research: “To identify novel trafficking mechanisms, new targeting motifs and new proteins that may play important roles in NMDAR regulation and synaptic development and plasticity that will open new frontiers for the development of disease-modifying therapeutic approaches for schizophrenia and other neuropsychiatric disorders. Because of the work supported by the NARSAD Young Investigator Grant, I have recently been awarded a Career Development Grant from the National Institute of Mental Health that will be supporting ongoing studies.”