D1 Medium Spiny Neurons display Spatially Segregated Differential Dopamine Sensitivity

Abstract ID 130212 Poster Board 369 The basal ganglia are a collection of subcortical nuclei that have been linked to movement, emotion, motivation, and learning. The striatum, which serves as the gateway to the basal ganglia circuit, receives dopaminergic neurons from the midbrain as well as other forms of input from various brain regions. The striatum is structurally and functionally segregated; the dorsal striatum is involved in habit formation whereas the ventral striatum is in goal-directed actions. Its main cell type is the medium spiny neurons (MSN), further divided into dopamine D1-receptor (D1R-MSNs) and D2-receptor MSNs (D2R-MSNs). The D1R is considered to have less affinity to dopamine (DA) (responding at the μM range) as compared to the high-affinity D2R (nM range). It has accordingly been assumed that D1R-MSNs sense phasic release of DA while D2R-MSNs sense lower levels of tonic DA release. Here, we study D1R-MSNs sensitivity to DA in striatal primary cultures derived from D1-Cre mice pups or wild-type E19 rat embryos and in acute brain slices transduced and stereotactically injected with the genetically encoded protein kinase A (PKA) sensor ExRai-AKAR2 respectively. By using live imaging epifluorescence and 2-photon microscopy, we can track PKA activity in individual neurons with high temporal and spatial resolution. Strikingly, we observe that individual D1R-MSNs exhibit differential responsiveness to DA with a subpopulation of D1R-MSNs responding to nanomolar concentrations of DA while other D1R-MSNs require micromolar concentrations. The D1R-MSNs display a DA-response spectrum. Moreover, this phenotype appears to be spatially segregated within the striatum when comparing between dorsal (DLS and DMS) and ventral striatum (NAc) and is seemingly characteristic of MSN when compared to other neuronal types. In addition to revealing a so far unappreciated dynamic signaling heterogeneity of D1R-MSNs, the data challenge the classical assumption of low-affinity D1Rs and high-affinity D2Rs. Furthermore, the differential regional distribution of the hypersensitive D1-MSNs could hint to its potential functional role on dopamine signalling. Further ongoing studies are targeted toward dissecting the underlying cellular mechanism and the putative role in DA-linked memory processes.