Project Summary

Steven Duffy, Ph.D. (Young Investigator 2005) of Samuel Lunenfeld Research Institute of Mount Sinai Hospital and the University of Toronto, plans to study in mice the potential relationship between low levels of D-serine, a regulator of the glutamatergic pathway in the brain, and schizophrenia. In the research, Dr. Duffy will test whether D-serine deficiency reduces synaptic plasticity in the hippocampus, amygdala, and nucleus accumbens, leading to schizotypic cognitive and sensory deficits. Dr. Duffy will decrease D-serine levels in mice by using drugs that block its synthesis or by disrupting the gene controlling synthesis. He will then measure synaptic plasticity and behavioral learning in the animal. He also will test if mice that lack the enzyme to break down D-serine and have elevated levels show enhanced plasticity/learning or are resistant to treatments that reduce D-serine. He will additionally assess if insufficient D-serine reduces the activity of inhibitory neurons (GABAergic interneurons), which normally suppress glutamatergic transmission in sensory pathways. Schizophrenics show a reduced ability to filter sensory stimuli. Finally, synaptic plasticity and gating will be examined in a mouse mutant lacking the NMDA binding protein Neto-1, as these animals replicate some schizotypic behaviors. Findings could help elucidate the mechanisms of cognitive and sensory impairments in schizophrenia and lead to better treatments.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia\Molecular

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