D1R- and D2R-Medium-Sized Spiny Neurons Diversity: Insights Into Striatal Vulnerability to Huntington’s Disease Mutation

Abstract

Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by an aberrant expansion of the CAG tract within the exon 1 of the HD gene, HTT. HD progressively impairs motor and cognitive capabilities, leading to a total loss of autonomy and ultimate death. Currently, no cure or effective treatment is available to halt the disease. Although the HTT gene is ubiquitously expressed, the striatum appears to be the most susceptible district to the HD mutation with Medium-sized Spiny Neurons (MSNs) (D1R and D2R) representing 95% of the striatal neuronal population. Why are striatal MSNs so vulnerable to the HD mutation? Particularly, why do D1R- and D2R-MSNs display different susceptibility to HD? Here, we highlight significant differences between D1R- and D2R-MSNs subpopulations, such as morphology, electrophysiology, transcriptomic, functionality, and localization in the striatum. We discuss possible reasons for their selective degeneration in the context of HD. Our review suggests that a better understanding of cell type-specific gene expression dysregulation within the striatum might reveal new paths to therapeutic intervention or prevention to ameliorate HD patients’ life expectancy.

Amyloid-β oligomers in the nucleus accumbens decrease motivation via insertion of calcium-permeable AMPA receptors

“…S8C – F ). Together with the reported involvement of D2-MSNs in (1) both reward and aversion 60 , and (2) greater susceptibility to excitotoxicity from cortical inputs 61 , 62 , we conclude that mPFC-NAcD2 projection is the synaptic substrate in AβO-induced low motivation.…”

Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease

“…After release in the striatum, dopamine acts on dopamine receptors expressed on medium spiny neurons [ 36 , 37 ]. Here, the dopamine D2 receptor (D2R) is associated with Gi protein, and its action is inhibitory.…”

“…How the expression of D3,4 receptors in the VTA dopaminergic system affect the pathological processes remains to be determined. Therefore, dopamine-releasing neurons are unlikely to cause excitotoxicity in medium spiny neurons [ 36 , 37 ]. In addition, nigrostriatal dopaminergic neurons themselves express D2R, and the released dopamine is thought to exert autocrine inhibitory effects on the excitability of these neurons [ 38 , 39 , 40 ].…”

A striatal SOM-driven ChAT-iMSN loop generates beta oscillations and produces motor deficits

“…A SOM-driven ChAT-iMSN loop for beta oscillation generation in striatum An exciting finding is the distinct spike waveforms in D1-and D2expression MSNs. Striatal MSNs have long been thought to be homogeneous in their somatodendritic morphology and physiology, but this concept was challenged by studies (Al-Muhtasib et al, 2018;Bergonzoni et al, 2021;Gertler et al, 2008). By using Drd1a-Cre and Drd2-Cre mice, we could distinguish and monitor firing activities in dMSNs and iMSNs in the striatum.…”