Dopamine-dependent long term potentiation in the dorsal striatum is reduced in the R6/2 mouse model of Huntington’s disease

The striatum is critically important in motor, cognitive and emotional functions, as highlighted in neurological disorders such as Huntington’s disease (HD) where these functions are compromised. The R6/2 mouse model of HD shows progressive motor and cognitive impairments and alterations in striatal dopamine and glutamate release. To determine whether or not dopamine-dependent neuronal plasticity is also altered in the dorsolateral striatum of R6/2 mice, we compared long term potentiation (LTP) and long term depression (LTD) in striatal slices from R6/2 mice with that seen in slices from wild type (WT) mice. In adult WT mice (aged 8–19 weeks), frequency-dependent bidirectional plasticity was observed. High frequency stimulation (four 0.5 s trains at 100 Hz, inter-train interval 10 s) induced LTP (134±5% of baseline), while low frequency stimulation (4 Hz for 15 min) induced LTD (80±5% of baseline). LTP and LTD were significantly blocked by the N-methyl-d-aspartic acid (NMDA) receptor antagonist d(−)-2-amino-5-phosphonopentanoic acid (D-AP5) (to 93±6% and 103±8% of baseline respectively), indicating that they are both dependent on NMDA glutamate receptor activation. LTP was significantly blocked by the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (98±8% of baseline), indicating that LTP is dependent on activation of dopamine D1-type receptors, whereas LTD was not significantly different (90±7%). In adult R6/2 mice (aged 8–19 weeks), LTP was significantly reduced (to 110±4% of baseline), while LTD was not significantly different from that seen in WT mice (85±6%). These data show that R6/2 mice have impaired dopamine-dependent neuronal plasticity in the striatum. As dopamine-dependent plasticity is a proposed model of striatum-based motor and cognitive functions, this impairment could contribute to deficits seen in R6/2 mice.