Somatostatin interneurons contribute towards increased striatal inhibition in the Q175 mouse model of Huntington's Disease

Huntington's Disease (HD) is a heritable neurological disorder that a ects cognitive and motor function in patients carrying the mutated huntingtin gene. In mouse models of HD, previous reports showed an increase in GABA neurotransmission to striatal medium-sized spiny neurons (MSNs). Here using optogenetics we examined the role of GABAergic, somatostatin (SOM)-expressing interneurons in HD using the Q175 (heterozygote) mouse model. These mice are a slowly progressing knock-in model carrying only one copy of the mutated HD allele and more closely mimic the human condition. Using patch clamp electrophysiology in voltage clamp mode, we recorded from MSNs in brains slices of presymptomatic (2 month) and symptomatic (8 and 12 month) Q175 mice and wildtype (WT) littermates. The amplitudes of responses evoked by activating SOM-expressing interneurons were similar in MSNs at both ages but di erences in response kinetics occurred in MSNs from symptomatic mice. Since SOM interneurons are constitutively active in striatal brain slices, we also examined the e ects of acutely silencing these neurons with halorhodopsin (eNpHR). Optically silencing SOM-expressing interneurons resulted in a decrease in the frequency of spontaneous IPSCs (sIPSCs) in a subset of MSNs from both WT and Q175 mice. The sIPSC frequency decrease during eNpHR activation was more pronounced in symptomatic Q175 MSNs compared to WT MSNs, suggesting that SOM interneurons contribute to the overall increased inhibition in HD MSNs. Additionally, CB1 receptors were activated with the agonist WIN 55,212-2 to determine if alterations in endocannabinoid-regulated neurotransmitter release is changed when SOM-expressing interneurons are activated. WIN-55 e ectively decreased the overall sIPSC frequency in both WT and Q175 MSNs. When selectively activating SOM-interneurons in the presence of WIN-55 the magnitude of the evoked IPSC in MSNs was decreased and this change was signi cantly reduced in symptomatic Q175 MSNs. Overall, these ndings show that aberrant neurotransmitter release from SOM interneurons contributes to the increased striatal inhibition found in HD mouse models and that dysregulation of the endocannabinoid system may contribute to this effect.