Decoding neuronal vulnerability: Multidimensional analysis of D1R ‐ and D2R ‐ medium‐sized spiny neurons in Huntington's disease

Abstract Understanding the molecular mechanisms driving selective neuronal vulnerability to different neurodegenerative disorders remains a crucial, unsolved question. Here, we explored the case of Huntington's disease (HD), where the striatum and, specifically, dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) medium‐sized spiny neurons (MSNs) exhibit differential susceptibility to the HTT CAG‐repeat expansion mutation, with D2R‐neurons being impacted earlier and more significantly. To unravel differences between D2R and D1R MSNs, we employed a multidimensional approach, integrating genomic, transcriptional, pattern distribution, and somatic instability analyses. Specifically, we used Htt CAG knock‐in mouse models harboring 18 ( Htt Q20 : “control”) or ~190 ( Htt Q175 : “HD”) consecutive CAG repeats, expressing tdTomato and EGFP under the control of Drd1 and Drd2 promoters, respectively. First, comprehensive genomic and transcriptomic analyses following fluorescence‐activated cell sorting (FACS) of dissociated striatal neurons revealed distinct gene expression profiles with a significant upregulation of oxidative phosphorylation and translation pathways in D1R‐positive neurons already at the pre‐symptomatic stage. These transcriptional changes were not accompanied by major copy number variations, as shown by parallel genomic analysis. Secondly, histological analyses revealed a greater proportion of D1R‐positive neurons compared to D2R‐positive neurons in HD mice, particularly in the ventral‐medial neostriatum, with D2R‐positive neurons presenting an increased nuclear accumulation of mutant huntingtin aggregates. In summary, our integrative study suggests that the distinct vulnerability of MSNs in HD might result from a combination of an early transcriptional compensatory response of D1R neurons together with specific susceptibility of D2R neurons.