Combinatorial topography and cell-type specific regulation of the ERK pathway by dopaminergic agonists in the mouse...

Therapeutic agents and drugs of abuse regulate the extracellular signal-regulated kinase (ERK) cascade signaling in the medium-sized spiny neurons (MSNs) of the striatum. However, whether this regulation is associated with specific cortical and thalamic inputs has never been studied. We used Drd2-EGFP BAC-transgenic mice to undertake a topographical and cell-type specific analysis of ERK phosphorylation and two of its downstream targets histone H3 and ribosomal protein S6 (rS6) in the dorsal striatum following injection of SKF81297 (D1R-like agonist), quinpirole (D2R-like agonist) or apomorphine (non selective DA receptor agonist). In striatal areas receiving inputs from the cingulate/prelimbic, visual and auditory cortex, SKF81297 treatment increased phosphorylation of ERK, histone H3 and rS6 selectively in EGFP-negative MSNs of Drd2-EGFP mice. In contrast, no regulation was found in striatal region predominantly targeted by the sensorimotor and motor cortex. Apomorphine slightly enhanced ERK and rS6, but not histone H3 phosphorylation. This regulation occurred exclusively in EGFP-negative neurons mostly in striatal sectors receiving connections from the insular, visual and auditory cortex. Quinpirole administration inhibited basal ERK activation but did not change histone H3 and rS6 phosphorylation throughout the rostrocaudal axis of the dorsal striatum. This anatomo-functional study indicates that D1R and D2R agonists produce a unique topography and cell-type specific regulation of the ERK cascade signaling in the mouse striatum, and that those patterns are closely associated with particular cortical and thalamic inputs. This work evidences the need of a precise identification of the striatal areas under study to further understand striatal plasticity.