title: Dopamine-dependent long term potentiation in the dorsal striatum is reduced in the R6/2 mouse model of Huntington's disease.
abstract: 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 D(1)-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.
authors.affiliation: Department of Physiology, Development and Neuroscience, Anatomy School, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
authors.forename: V W S
authors.initials: VW
authors.lastname: Kung
authors.forename: R
authors.initials: R
authors.lastname: Hassam
authors.forename: A J
authors.initials: AJ
authors.lastname: Morton
authors.forename: S
authors.initials: S
authors.lastname: Jones
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000503:physiopathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011810:Quinoxalines / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011810:Quinoxalines; C056723:FG 9041; D004298:Dopamine