title: Changes in Dopamine Signalling Do Not Underlie Aberrant Hippocampal Plasticity in a Mouse Model of Huntington's Disease.
abstract: Altered dopamine receptor labelling has been demonstrated in presymptomatic and symptomatic Huntington's disease (HD) gene carriers, indicating that alterations in dopaminergic signalling are an early event in HD. We have previously described early alterations in synaptic transmission and plasticity in both the cortex and hippocampus of the R6/1 mouse model of Huntington's disease. Deficits in cortical synaptic plasticity were associated with altered dopaminergic signalling and could be reversed by D1- or D2-like dopamine receptor activation. In light of these findings we here investigated whether defects in dopamine signalling could also contribute to the marked alteration in hippocampal synaptic function. To this end we performed dopamine receptor labelling and pharmacology in the R6/1 hippocampus and report a marked, age-dependent elevation of hippocampal D1 and D2 receptor labelling in R6/1 hippocampal subfields. Yet, pharmacological inhibition or activation of D1- or D2-like receptors did not modify the aberrant synaptic plasticity observed in R6/1 mice. These findings demonstrate that global perturbations to dopamine receptor expression do occur in HD transgenic mice, similarly in HD gene carriers and patients. However, the direction of change and the lack of effect of dopaminergic pharmacological agents on synaptic function demonstrate that the perturbations are heterogeneous and region-specific, a finding that may explain the mixed results of dopamine therapy in HD.
authors.affiliation: Huntington's Disease Research Forum, Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, MK76AA, UK. glenn.dallerac@college-de-france.fr.|CIRB, CNRS UMR 7241, INSERM U1050, Collège de France, 75005, Paris, France. glenn.dallerac@college-de-france.fr.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Dallérac
authors.affiliation: Huntington's Disease Research Forum, Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, MK76AA, UK.|University College London, Neuroscience, Physiology and Pharmacology, Gower Street, London, WC1E 6BT, UK.
authors.forename: Damian M
authors.initials: DM
authors.lastname: Cummings
authors.affiliation: Huntington's Disease Research Forum, Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, MK76AA, UK.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Hirst
authors.affiliation: Huntington's Disease Research Forum, Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, MK76AA, UK.|Department of Neurology & Centre for Applied Neurogenetics, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2255, Wesbrook Mall, Vancouver, V6T 1Z3, Canada.
authors.forename: Austen J
authors.initials: AJ
authors.lastname: Milnerwood
authors.affiliation: Huntington's Disease Research Forum, Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, MK76AA, UK. kerry.murphy@open.ac.uk.
authors.forename: Kerry P S J
authors.initials: KP
authors.lastname: Murphy
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology*; D036881:Long-Term Synaptic Depression; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D004298:Dopamine
keywords: Electrophysiology; Huntingtin; LTD; Neurodegeneration; Polyglutamine; R6/1; Synaptic plasticity