Geoffrey Bamford

bamford@u.washington.edu
Associate Professor, Departments of Neurology, Pediatrics and Psychology

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The basal ganglia play an important role in voluntary movement and substance dependence. Excitatory glutamatergic corticostriatal projections from the cerebral cortex innervate the basal ganglia at the striatal medium spiny neuron, which also receives modulatory dopamine projections from midbrain nuclei. Both dopamine and glutamate have been implicated in numerous neuropsychiatric disorders including Parkinson's disease, Huntington's disease and substance dependence. We have recently shown that dopamine depresses the release of glutamate from a subset of cortical terminals providing filtering of cortical information to the striatum and that alterations in striatal dopamine release lead to long-term changes in striatal excitation mediated by dopamine receptor hypersensitivity and neuroplasticity. Using mouse models for dopamine depletion and dopamine excess, we study the effect of altered dopamine availability on striatal synaptic plasticity. We define the mechanisms underlying these neuroplastic alterations and we determine if drug-induced behaviors are determined by such adaptations. We utilize a newly developed imaging technique that allows direct visualization of release from corticostriatal presynaptic terminals in murine striatal slice preparations. These optical studies are integrated with whole-cell patch clamp recordings that delineate the characteristics of the corticostriatal pathway and the effects of dopamine transmission at the medium spiny neuron. In vivo manipulations of transgenic and wild-type mice provide models with which to investigate synaptic plasticity that occurs with dopamine depletion and dopamine excess. The outcome of our investigations demonstrate how alterations in dopamine release produce corticostriatal plasticity and show mechanistically how aberrant striatal excitation might lead to certain neuropsychiatric signs and symptoms. Our projects will provide further insights into pharmacological alternatives for the treatment of movement disorders and addiction.