Abstract

Medium spiny neurons (MSNs) provide the principal output for the dorsal striatum. Those that express dopamine D2 receptors (D2+) project to the globus pallidus and inhibit movement, whereas those that express dopamine D1 receptors (D1+) project to the substantia nigra pars reticulata and facilitate movement. Imbalances in the output from these two pathways have been implicated in a wide range of neurological disorders including Parkinson's disease, Huntington's disease, dyskinesia, Tourette's syndrome, drug addiction, and obsessive compulsive disorder. Thus, elucidating mechanisms to selectively regulate these pathways holds significant promise to identify targets for new and much needed treatments for striatal-related disorders. In this thesis, I identify and characterize a novel tonic GABA_A receptor-mediated conductance. Using whole-cell recordings performed in slices prepared from two strains of bacterial artificial chromosome transgenic mice in which expression of enhanced green fluorescent protein is driven by the promoters for D1 and D2 receptors, I demonstrate that tonic GABA_A receptor-mediated currents are significantly larger in D2+ MSNs than in D1+ MSNs. Additionally, synaptic spill-over produces the ambient GABA responsible for activating these receptors. Furthermore, combined evidence from whole-cell and excised patch recordings suggest that the divergence in GABA tonic current magnitude between the two MSN populations is mediated by differences in GABA_A receptor sensitivity. Recordings from MSNs in α1-/- mice, pharmacological analysis of tonic currents, and immunofluorescent labeling with confocal microscopy suggests that α5 subunit-containing GABA_A receptors both mediate the GABA tonic current and shown higher expression levels in D2+ MSNs. However, whole-cell single and paired recordings suggest that phosphorylation states contribute to difference in GABA_A receptor sensitivity between D1+ and D2+ MSNs. Furthermore, in this thesis I describe an unprecedented methodology for future investigations of phosphorylation effects on ion channel kinetics. Interestingly, results from whole-cell and cell-attach recordings demonstrate that unlike tonic GABA currents described in other brain regions, those found in MSNs may serve to increase cell excitability. In sum, these results demonstrate that receptors mediating GABA tonic current, selectively expressed in D2+ MSNs, may serve as targets for innovative therapeutics for the debilitating symptoms of many striatal-related disorders.