Optogenetic control of striatal fast-spiking interneurons in Huntington’s disease mouse models
Abstract SFN 2012
Résumé
Huntington's disease (HD), an inherited neurodegenerative disorder caused by a mutation in the IT15 gene, is characterized by massive degeneration of striatal medium-sized spiny neurons (MSNs). MSNs are gamma-aminobutyric acid (GABA) neurons that project, via the direct and the indirect pathways, to the globus pallidus and substantia nigra. They are affected early in HD while striatal interneurons are relatively spared of the degenerative process. In HD models, spontaneous GABA synaptic activity onto MSNs is increased and one possible source of this increased inhibition is from striatal interneurons. Parvalbumin (PV)-expressing interneurons are the most abundant, display fast-firing properties and mediate feed-forward inhibition. In the present study, we examined the response of MSNs to PV interneuron activation or inhibition in the R6/2 mouse model of HD using optogenetics. We used adeno-associated virus type 2 (AAV2) to express channelrhodopsin-2 H134R (ChR2) or enhanced halorhodopsin (eNpHR) in the striatum of one month old R6/2 and Wild Type (WT) mice crossed with PV-CRE mice to express the construct only in PV-positive interneurons. The expression of these proteins was visualized by enhanced yellow fluorescent protein (EYFP) (ChR2-EYFP, eNpHR-EYFP). These constructs have two flox sites that lead to specific expression in PV interneurons by the CRE recombinase sequence. Blue (470 nm) or yellow (590 nm) light was used to activate or inhibit the PV-positive cells. We found that the level of expression of ChrR2-EYFP and eNpHR-EYFP fluorescence intensity and injection size were not significantly different in the R6/2 and WT PV-CRE mice. Electrophysiological recordings in current and voltage clamp modes, one month after injections, from ChR2-and eNpHR-EYFP PV interneurons using light stimulation validated construct expression. Recordings from MSNs demonstrated that activation of PV-positive neurons produced differential kinetics of GABAergic responses of MSNs obtained from R6/2 and WT mice. These findings suggest that PV interneurons may contribute to differential GABAergic responses in MSNs in HD.