Project Summary

Robert C. Malenka, M.D., Ph.D. (Distinguished Investigator 2007) of Stanford University, aims to use an animal model to study the role of the brain’s striatum in mental illness. Evidence suggests the striatum plays a role in depression, schizophrenia and obsessive-compulsive disorder. Moreover, the striatum receives dense dopaminergic innervation, and dysfunction of the dopaminergic modulation of striatal circuits has been associated with both depression and schizophrenia. The striatum is divided into dorsal and ventral components, but appears homogeneous because >95 percent of its cells are medium spiny neurons (MSNs). But cortical and limbic afferents make excitatory synapses onto two distinct populations of MSNs that are part of two independent parallel circuits known as the direct (or striatonigral) and indirect (striatopallidal) pathways. These two MSN populations differ in their neurotransmitter receptor and neuropeptides expression. A limitation to understanding striatal circuitry has been the lack of knowledge about possible physiological differences between the different MSN populations, which have been assumed to have similar, if not identical, synaptic and electrophysiological properties. However, a newly engineered transgenic mouse allows scientists to now see cell-type specific expression of green fluorescent protein in distinct neuronal subpopulations, including MSNs of the direct and indirect pathways in both dorsal and ventral striatum. These mice provide a previously unavailable resource to characterize the cellular and synaptic properties of neurons in these subpopulations. Indeed, Dr. Malenka has found (Nature, in press) clear differences in the function and plasticity of synapses on dopamine Dl receptor-expressing, direct pathway MSNs versus D2 receptor-expressing indirect pathway MSNs. Furthermore, the modulation of synaptic plasticity by dopamine appears to be different in these distinct MSN populations. In this proposal, Dr. Malenska plans on studying the following hypothesis: that excitatory synapses on MSNs of the indirect and direct pathways exhibit different properties and that these differences are functionally important both for adaptive brain functions and during brain disorders, such as depression. Results may lead to a better understanding of the pathophysiology of mental illness and to new approaches for drug development.

Program Area: BASAL GANGLIA DISEASES

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