Interactions of D1-dopamine receptors with functionally distinct NMDA receptors in striatum

The striatum is the main input nucleus of the basal ganglia, a group of subcortical structures critically involved in the control of movement and cognitive function. This structure receives excitatory glutamate input and modulatory dopamine (DA) input. How these two neurotransmitter systems interact in striatal efferent neurons largely governs basal ganglia activity and function. The N-methyl-D-aspartate receptor (NMDAR) is a subtype of glutamate-gated ion channels which is comprised of multiple and different subunits. In striatum, the NR2A subunit of the NMDAR shows a distinct medial-to-lateral gradient, with greater expression laterally. Varied levels of NR2A subunit in expression systems and across development give rise to NMDARs with different biophysical and pharmacological properties. However, whether such differences occur in the same neuronal type at the same developmental timepoint in different regions of the striatum has not been determined. The studies presented in this dissertation therefore were designed to test the hypothesis that there are functionally distinct NMDARs in dorsolateral versus ventromedial striatum and that these receptors are differentially modulated by D1-DA receptor activation. The results demonstrate that NMDARs in different regions of striatum are functionally distinct. The data also suggest that these NMDARs may be differentially affected by D1-DA receptor activation. Finally, the data show that a partial loss of striatal DA alters D1-DA receptor signaling in striatum, including differential modulation of NMDARs in ventromedial striatum. The data presented in this dissertation are the first to show electrophysiologically that NMDARs in striatum are functionally distinct and that striatal efferent neuron function is altered as a consequence of partial DA loss. This information may ultimately lead to improved treatments for long-term consequences of psychostimulant abuse and other basal ganglia disorders, including Parkinson's disease and schizophrenia.