Cholesterol nanoparticles partially rescue the alterations in synaptic phenotype of the R6/2 mouse model of Huntington's Disease

Previous studies in the R6/2 mouse model of Huntington's disease (HD) have demonstrated key alterations in membrane properties and synaptic transmission of striatal medium-sized spiny neurons (MSNs) in behaviorally phenotypic mice. These changes include: lower frequency of spontaneous excitatory postsynaptic currents (sEPSCs), higher frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), increased membrane input resistance, and decreased cell capacitance. Enzymatic analyses show that brains of symptomatic R6/2 mice also have reduced total sterol mass and reduced translocation of sterol regulatory element-binding proteins, leading to a decrease in transcription of genes involved in the cholesterol (Chol) biosynthesis pathway. The present study examines how Chol supplementation using glycopeptide-modified nanoparticles (g7-Nps), specifically engineered to cross the blood-brain barrier after systemic administration in rodents, affects synaptic transmission and basic membrane properties of striatal MSNs in symptomatic R6/2 mice compared to their wildtype (WT) littermates. We show that g7-Nps injected systemically enter the brain and localize in neurons and glia in the cortex and striatum within 4 h after an i.p. injection and persist for several weeks in R6/2 and WT mice. In addition, MSNs of R6/2 mice injected with Chol-g7-Nps (8 injections over a four-week period) show a less pronounced increase in sIPSC frequency and a trend towards an increase in sEPSC frequency compared to R6/2 mice that received either empty-g7-Nps or saline injections. Furthermore, basic membrane properties of MSNs from R6/2 mice treated with Chol-g7-Nps show a trend towards decreased membrane input resistance and increased cell capacitance compared to R6/2 mice that did not receive Chol supplementation. There were no significant differences between WTs that received Chol-g7-Nps, empty-g7-Nps, or saline injections. These results suggest that repeated administrations of Chol-g7-Nps produce a partial rescue of the alterations in membrane properties and the synaptic phenotype of R6/2 mice. In conclusion, the results demonstrate the therapeutic potential of a nanomedicine-based approach using g7-Nps to deliver specific drugs that could modify HD symptoms, as well as the use of Chol to reverse the cascade of synaptic alterations associated with this diseas