Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow-progression model of Huntington's disease

- 35% loss of dendritic spines in MSNs in the absence of dendritic changes and neuronal loss in aged BACHD mice
- Increased amplitude of the sEPSCs in MSNs in aged BACHD mice
- Low expression of striatum-specific GPR88 and different compositions of AMPAR subunits in aged BACHD mice
- Increased strength of the synapses may compensate for spine loss in MSNs of aged BACHD mice.
- Homeostasis mechanisms observed in this study in aged BACHD mice may explain the late onset of HD symptoms.

Huntington's disease (HD) is an autosomal dominant disease that develops in midlife (~ 40 years-old at onset) and then progresses slowly. It is still unclear how striatal medium spiny neurons (MSNs), the most vulnerable neurons in HD, maintain their function for decades despite the chronic expression of mutant huntingtin (mHTT). In this study, we used aged BACHD mice, a HD model expressing the full-length human mHTT gene, to investigate the molecular, morphological and functional properties of striatal MSNs.We report that the density of dendritic spines in MSNs is substantially lower in aged BACHD mice than in wild-type (WT) mice, in the absence of major dendritic changes and neuronal loss. This spine loss is accompanied by changes in transcription, resulting in a low expression of the striatum-specific G protein-coupled receptor 88 (Gpr88) as well as a reorganization of the composition of AMPAR subunits (high Gria1/Gria2 mRNA ratio). We also detected functional changes in BACHD MSNs. Notably, BACHD MSNs were hyperexcitable and the amplitude of AMPAR-mediated synaptic currents was higher than in WT MSNs. Altogether, these data show that both the intrinsic properties and the strength of the remaining synapses are modified in MSNs with low dendritic spine density in aged BACHD mice. These homeostatic mechanisms may compensate for the substantial loss of synaptic inputs and thus alleviate the deleterious effects of mHTT expression on the activity of MSNs and also possibly on the motor phenotype in aged BACHD.