This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A large amount of research provides compelling supportive evidence for a dysfunction in the brain s glutamate signaling system in major depressive disorder (MDD). This postulate is based on (1) evidence of abnormal level of glutamate in the brain of major depressive subjects as revealed by in vivo imaging techniques; (2) postmortem evidence of altered immunoreactivities of proteins engaged in glutamate transmission in depression; (3) antidepressant-like effects of agents decreasing glutamate signaling seen in laboratory animals and humans. Our preliminary investigations using postmortem human brain tissue have provided evidence of abnormalities in indices of glutamatergic signaling in the brainstem from subjects with MDD. In conjunction with research by other laboratories, our preliminary findings have demonstrated that abnormal glutamatergic neuronal activity in MDD can be revealed by neurochemical abnormalities in the postmortem brain. An area of the brain where glutamate is a critical component of neuronal circuitry and where gross neuropathology has been reproducibly demonstrated in MDD is the hippocampus. Reductions in hippocampal volume and neuropil have been reported for MDD subjects. Interestingly, in laboratory animals, brain glutamate levels are increased after exposure to stress and chronic stress produces hippocampal atrophy. Based on these findings and our preliminary data, we hypothesize that at least part of the pathology of the hippocampus in MDD is triggered by elevated glutamate signaling. This elevated signaling will be revealed by abnormalities in glutamate indices, such as glutamate transporters, receptors and their intracellular-associated molecules, in the hippocampus. To achieve these goals postmortem brain tissues from MDD subjects and carefully matched psychiatrically normal controls will be utilized. Diagnoses are made via a rigorous psychiatric autopsy program under the direction of Dr. Craig Stockmeier. Overall, the proposed research will elucidate the molecular underpinning of glutamate pathology and may yield new targets for novel therapeutic approaches to treatment of depressive disorders.
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