Striatal Neurons Expressing D1 and D2 Receptors are Morphologically Distinct and Differently Affected by Dopamine Denervation in Mice

Abstract

The loss of nigrostriatal dopamine neurons in Parkinson’s disease induces a reduction in the number of dendritic spines on medium spiny neurons (MSNs) of the striatum expressing D1 or D2 dopamine receptor. Consequences on MSNs expressing both receptors (D1/D2 MSNs) are currently unknown. We looked for changes induced by dopamine denervation in the density, regional distribution and morphological features of D1/D2 MSNs, by comparing 6-OHDA-lesioned double BAC transgenic mice (Drd1a-tdTomato/Drd2-EGFP) to sham-lesioned animals. D1/D2 MSNs are uniformly distributed throughout the dorsal striatum (1.9% of MSNs). In contrast, they are heterogeneously distributed and more numerous in the ventral striatum (14.6% in the shell and 7.3% in the core). Compared to D1 and D2 MSNs, D1/D2 MSNs are endowed with a smaller cell body and a less profusely arborized dendritic tree with less dendritic spines. The dendritic spine density of D1/D2 MSNs, but also of D1 and D2 MSNs, is significantly reduced in 6-OHDA-lesioned mice. In contrast to D1 and D2 MSNs, the extent of dendritic arborization of D1/D2 MSNs appears unaltered in 6-OHDA-lesioned mice. Our data indicate that D1/D2 MSNs in the mouse striatum form a distinct neuronal population that is affected differently by dopamine deafferentation that characterizes Parkinson’s disease.

Striatal synapses, circuits, and Parkinson's disease

“…However, the segregation is not complete. A small fraction of SPNs co-express D1Rs and D2Rs and constitute a distinct population that is differentially altered in Parkinson’s disease [6,7]. …”

Striatal Local Circuitry: A New Framework for Lateral Inhibition

“…It is clear now that this dichotomy is an over-simplification of the existing subtypes of SPNs and that the segregation is imperfect. For example, a subset of SPNs co-express both D1 and D2 receptors in the adult striatum (~2–5% dorsal striatum,~6–7% in the NAc core, ~12–15% in the NAc shell) that are morphologically distinct from other SPNs and have a poorly understood function (Bertran-Gonzalez et al, 2008; Gagnon et al, 2017). Furthermore, a recent study shows large cell-to-cell variability in the pattern of overall gene expression within each subclass of SPN (Gokce et al, 2015).…”

Characterizing the binding of dopamine D1–D2 receptors in vitro and in temporal and frontal lobe tissue total protein

“…Subsequently, the number of D1-D2 heteromers was shown to increase with age in the striatum [13]. Specifically, the D1 and D2 receptors are co-expressed primarily in medium spiny neurons of the nucleus accumbens, globus pallidus, and caudate putamen; further, the D1-D2 heteromer was identified in striatal neurons that contain both dynorphin and enkephalin in rats [15] and dynorphin in mice [16]. Specifically, the D1 and D2 receptors are co-expressed primarily in medium spiny neurons of the nucleus accumbens, globus pallidus, and caudate putamen; further, the D1-D2 heteromer was identified in striatal neurons that contain both dynorphin and enkephalin in rats [15] and dynorphin in mice [16].…”

“…The D1-D2 heteromer was identified in transfected cells and in vivo [14] and later discovered to be co-localized in presynaptic terminals and within cell bodies within a specific neuronal subpopulation in the basal ganglia [15]. While the reported proportion of medium spiny neurons that co-express D1 and D2 varies widely depending upon the methods used and species studied, a recent report estimates the total percentage to be 0.8-2.4%, distributed heterogeneously, utilizing transgenic mice expressing specific fluorescent protein reporters [16]. While the reported proportion of medium spiny neurons that co-express D1 and D2 varies widely depending upon the methods used and species studied, a recent report estimates the total percentage to be 0.8-2.4%, distributed heterogeneously, utilizing transgenic mice expressing specific fluorescent protein reporters [16].…”