Altered function of Parvalbumin expressing interneurons in mouse models of Huntington’s disease
Résumé
Huntington's disease (HD), a neurodegenerative disorder caused by a mutation in the HD gene, is characterized by dysfunction and ultimate degeneration of striatal medium-sized spiny neurons (MSNs). Although it was thought that interneurons were relatively spared in HD, recent studies have shown signi cant alterations in parvalbumin (PV)-expressing interneurons. These interneurons display fast-ring properties and mediate feed-forward inhibition in the striatum. Previously we showed using optogenetics to speci cally activate PV-expressing interneurons that alterations in GABAergic input from PV-expressing interneurons may contribute to MSN dysfunction in HD. Here we used a similar optogenetic paradigm to further examine alterations in PV-expressing interneuron inputs to MSNs in the R6/2 and the Q175 models. We examined whether PV-expressing interneuron responses in R6/2 mice were di erentially a ected in direct versus indirect pathway MSNs. R6/2 mice were crossed with PV-Cre mice and D1 tomato mice to identify direct and indirect pathway MSNs. The data show that PV-expressing interneurons induced a larger GABAergic response in direct compared to indirect pathway wildtype (WT) MSNs. In symptomatic R6/2 mice, direct pathway MSNs displayed a smaller response compared to the WT direct pathway response. Q175 mice were crossed with PV-Cre mice to examine the progression of response alterations in MSNs at 2 (presymptomatic) and 8 (beginning of symptomatic stage) months. In 2 month Q175 mice, there were no di erences between genotypes. In contrast, in 8 month Q175 mice, activation of striatal PV-expressing interneurons evoked signi cantly smaller MSN GABAergic responses with a faster decay time than in WTs. We also compared the e ects of activation of endocannabinoid receptor 1 (CB1) in the two models. The CB1 agonist, WIN 55,212-2 decreased PV-induced responses in both Q175 and WT MSNs but not in the symptomatic R6/2 MSNs as previously described. Together, these ndings suggest that alterations in function of PV-expressing interneurons di er in the R6/2 and Q175 mice but will contribute to neuronal microcircuit alterations in the striatum.