Glutamatergic Dysfunction and Schizophrenia

Mclean Hospital, Belmont MA

Investigators

Linked publications & trials

Abstract

The Center has focused on glutamatergic mechanisms, especially in the hippocampus, in experimental[unreadable] models to explore testable hypotheses about their involvement in the cognitive manifestations of[unreadable] schizophrenia. The over-arching hypothesis of the Center has been that hypofunction of a subpopulation of[unreadable] brain NMDA receptors contributes to the clinical features of schizophrenia. During the last 5 years, significant[unreadable] advances have been made that lend support to our hypotheses, including the development of animal models[unreadable] that more faithfully recreate the synaptic pathology of the disorder, the characterization of hippocampal[unreadable] memory processes in rodents, such as transitive inference, that are relevant to schizophrenia, and the[unreadable] identification of risk genes by others that affect glutamatergic neurotransmission. The Center consists of[unreadable] seven Projects and 3 Cores. Project 1: Benes has shown that amygdalar picrotoxin injection recreates in[unreadable] hippocampal CA2/3 neuropathologic changes similar to those in schizophrenia and will define the molecular[unreadable] and electrophysiologic consequences of this lesion. Project 2: Lisman will examine the interaction between[unreadable] dopamine and NMDA receptors in the hippocampus and their role in novelty detection, which is impaired in[unreadable] schizophrenia. Project 3: Eichenbaum will characterize the NMDA receptor's role in components of[unreadable] pragmatic memory known to be affected in schizophrenia. Project 4: Coyle has created mice with conditional[unreadable] knockouts of seririe racemase and glutamate carboxypeptidase II to determine the electrophysiologic and[unreadable] behavioral consequences of suppressing their expression jn young adulthood. Furthermore, they will[unreadable] examine the mechanisms of action of the protein encoded by G72, a risk gene in schizophrenia that[unreadable] reputedly enhances D-serine catabolism. Project 5: Yurgelun-Todd will use MRS to measure NAA and[unreadable] NAAG levels in the brains of schizophrenic subjects and animal models, and on BOLD signal changes in[unreadable] fMRI. Project 6: Goff will determine the efficacy of D-serine in schizophrenic patients receiving concurrent[unreadable] antipsychotics and will correlate treatment responses to relevant genotypes such as GCPII, G72 and GRM3.[unreadable] Project 7: Javitt will evaluate the effects of D-serine treatment on sensory processing measures and higher[unreadable] neurocognitive disturbances in prodromal and established schizophrenics. Computational Core: Hasselmo[unreadable] will develop computational models based on the findings of the Center. Biostatistical Core: Lange will[unreadable] provide statistical support for Center investigators. Administrative Core: Coyle will provide scientific[unreadable] oversight and budgetary administration to insure that the goals are achieved.