Nuclear Receptor Nr4a1 Regulates Striatal Striosome Development and Dopamine D Receptor Signaling.

The GABAergic medium-size spiny neuron (MSN), the striatal output neuron, may be classified into striosome, also known as patch, and matrix, based on neurochemical differences between the two compartments. At this time, little is known regarding the regulation of the development of the two compartments. , primarily described as a nuclear receptor/immediate early gene involved in the homeostasis of the dopaminergic system, is a striosomal marker. Using -overexpressing and -null mice, we sought to determine whether Nr4a1 is necessary and/or sufficient for striosome development. We report that and , and mRNA levels are correlated. In the absence of Nr4a, there is a decrease in the percentage of striatal surface area occupied by striosomes. Alterations in expression leads to dysregulation of multiple mRNAs of members of the dopamine receptor D signal transduction system. Constitutive overexpression of decreases both the induction of phosphorylation of ERK after a single cocaine exposure and locomotor sensitization following chronic cocaine exposure. overexpression increases MSN excitability but reduces MSN long-term potentiation. In the resting state, type 5 adenylyl cyclase (AC5) activity is normal, but the ability of AC5 to be activated by Drd1 G-protein-coupled receptor inputs is decreased. Our results support a role for in determination of striatal patch/matrix structure and in regulation of dopaminoceptive neuronal function.