Nuclear Receptor Nr4a1 Regulates Striatal Striosome Development and Dopamine D₁ 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. Nr4a1, primarily described as a nuclear receptor/immediate early gene involved in the homeostasis of the dopaminergic system, is a striosomal marker. Using Nr4a1-overexpressing and Nr4a1-null mice, we sought to determine whether Nr4a1 is necessary and/or sufficient for striosome development. We report that in vivo and in vitro, Nr4a1 and Oprm1 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 Nr4a1 expression leads to dysregulation of multiple mRNAs of members of the dopamine receptor D₁ signal transduction system. Constitutive overexpression of Nr4a1 decreases both the induction of phosphorylation of ERK after a single cocaine exposure and locomotor sensitization following chronic cocaine exposure. Nr4a1 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 Nr4a1 in determination of striatal patch/matrix structure and in regulation of dopaminoceptive neuronal function.