Optogenetic control of parvalbumin-expressing interneurons in the R6/2 and Q175 mouse models of Huntington’s disease
Résumé
Huntington's disease (HD), a neurodegenerative disorder caused by a mutation in the IT15 gene, is characterized by dysfunction and ultimate degeneration of striatal medium-sized spiny neurons (MSNs) and cortical pyramidal neurons (CPNs). Although it was thought that interneurons were relatively spared in HD, recent studies have shown a significant loss of parvalbumin (PV)-expressing interneurons that increases with severity of the disease. PV-expressing interneurons display fast-firing properties and mediate feed-forward inhibition in the striatum as well as limit CPN excitability. MSNs display an increase in GABAergic activity whereas CPNs show an increase in glutamatergic activity in several HD mouse models as the phenotype progresses. We hypothesized that PV-expressing interneurons may contribute to MSN and CPN dysfunction in HD. Previously we demonstrated significant changes in PV-expressing interneuron-evoked inhibitory responses in MSNs in symptomatic R6/2 mice using optogenetics. Here, using a similar optogenetic paradigm, we further examined alterations in PV-expressing interneuron inputs to MSNs and to CPNs in the R6/2 model. Additionally, we examined PV-expressing interneuron evoked responses in another HD mouse model, the Q175 knock-in, which has a more protracted course of phenotype progression. R6/2 and Q175 mice were crossed with PV-Cre mice and subsequently injected with a Cre-dependent channelrhodopsin-2 (ChR2) construct using viral delivery. MSNs or layer II/III CPNs were recorded in slices in voltage clamp mode. In symptomatic R6/2 mice, MSN recordings showed that activation of striatal PV-expressing interneurons induced significantly larger evoked GABAergic responses with faster kinetics than responses from wildtype 4/6/2020