Abstract SFN 2013

Abstract

Abstract SFN 2013International audienceHuntington'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) and loss of layers II, III and V cortical pyramidal neurons (CPNs). In both cases, interneurons are relatively spared of the degenerative process. Parvalbumin (PV)-expressing interneurons, also called fast-spiking interneurons (FSI), display fast-firing properties and mediate feed-forward inhibition in the striatum. They represent an abundant and homogenous population of GABAergic interneurons in the striatum. In contrast, cortical PV-interneurons are a heterogeneous population. They are mainly GABAergic large basket cells displaying FSI properties that project onto CPNs. We examined PV interneuron outputs in striatum and cortex in symptomatic R6/2 mice. We used adeno-associated virus type 2 to express channelrhodopsin-2 H134R (ChR2) in the striatum or in the sensorimotor cortex of one month old R6/2 and wildtype (WT) mice crossed with PV-CRE mice. The construct is only inserted in PV-positive cells by CRE recombination. The expression of these proteins was visualized by enhanced yellow fluorescent protein (EYFP) (ChR2-EYFP). Blue light (470 nm) was used to activate the EYFP-positive cells. Dorsolateral striatal MSNs and layer II/III CPNs were recorded in voltage clamp mode. Recordings from MSNs demonstrated that activation of PV-positive neurons induced significantly larger amplitude GABAergic responses in R6/2s compared to WTs in 60 day-old mice. R6/2 responses also displayed more rapid rise and decay times than those of WTs. There were no significant differences in responses from CPNs between WT and R6/2 mice. Interestingly, the ChR2-activated PV-positive cells induced higher GABAergic response amplitudes in CPNs than MSNs in a genotype-independent manner. Together, these data suggest that PV-expressing interneurons differentially affect MSNs in the striatum of R6/2 and WT mice but may not produce similar differential effects on CPNs. This could be explained by the fact that PV interneurons in the cortex are a more heterogeneous population than in the striatum or they are differentially affected in HD