Nuclear receptor Nr4a1 regulates striatal striosome development and dopamine D1 receptor signaling

Abstract

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. Up to date, little is known regarding the regulation of 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 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 map kinase (ERK) after a single cocaine exposure and locomotor sensitization following chronic cocaine exposure. Nr4a1 overexpression increases MSN excitability but reduces MSN long-term potentiation (LTP). In the resting state, adenylyl cyclase V (ACV) activity is normal, but the ability of ACV 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.

Significance statement This study provides insight on the role of Nr4a1, a transcription factor belonging to the family of orphan nuclear receptors Nurr, in the development of the striatal striosomal compartment and in the regulation of dopaminoceptive neuronal function. We show that alteration of Nr4a1 expression impacts the expression of striosome markers in vivo and in vitro, suggesting that Nr4a1 is necessary for full striosome development. Moreover, Nr4a1 overexpression alters Drd1 signal transduction at multiple levels resulting in reduced phosphorylation of ERK after cocaine, reduced induction of LTP, and absence of locomotor sensitization following chronic cocaine. These results indicate that the pathways regulated by Nr4a1 may represent novel, druggable approaches to pathological states such as levodopa induced dyskinesia and cocaine sensitization.