Optogenetics reveal alterations in dopamine neurotransmission in the YAC128 mouse model of Huntington’s disease
Résumé
Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by a mutation in the HTT gene producing an expansion of glutamine repeats. The principal neuropathology of HD is a loss of striatal and cortical projection neurons, leading to a progressive disconnection between the cortex and striatum. Dopamine (DA) modulation of glutamatergic inputs also is disrupted in HD mouse models. Previous studies using the YAC128 mouse model of HD have provided evidence that excess DA may be present early in disease progression (2 months of age) whereas DA is depleted in the late stages (11 months). The present study used channelrhodopsin (ChR2) to selectively activate DA inputs to identified striatal medium-sized spiny neurons (MSNs) in triple transgenic YAC128 mice and control littermates (WT) expressing Cre recombinase under the tyrosine hydroxylase promoter and DsRed fluorescence under the DA D1 receptor promoter, which identifies direct-pathway MSNs. ChR2 was stereotaxically injected into the substantia nigra pars compacta of mice at 2 and 11 months of age. Fast-scan cyclic voltammetry demonstrated no significant differences in amplitude of DA release between WT and YAC128 mice at 2 months of age. However, the decay time of DA release was significantly increased in slices from YAC128 mice, suggesting that alterations in the DA transporter occur. Addition of quinpirole, a D2 agonist, had smaller effects on DA release in YAC128 mice indicating a possible reduction of autoreceptor function. Furthermore, inhibiting DA reuptake with GBR 12935 produced smaller effects on release and decay time in 2 month-old YAC128 mice. In 11 month-old mice, the alterations in kinetics of
DA release in YAC128 were less evident. Whole-cell patch clamp electrophysiological recordings in 2 month-old mice showed that ChR2-evoked release of DA had differential effects on synaptic transmission of D1 and D2 receptor-expressing MSNs. Release of DA increased the frequency of spontaneous excitatory postsynaptic currents (sEPSC) of D1-MSNs from WT mice but had no effect on sEPSC frequency of D1-MSNs from YAC128 mice. In contrast, DA
release decreased EPSC frequency of D2-MSNs from both WT and YAC128 mice. Together, these data demonstrate that DA neurotransmission, particularly DA transporter and modulatory function, are altered early in disease progression. Slower decay times of DA release may contribute to increases in stereotypies observed in HD mice. Furthermore, treatments aimed at reducing the presence of DA at the synaptic cleft might help normalize behavioral alterations