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Changes in Dopamine Signalling Do Not Underlie Aberrant Hippocampal Plasticity in a Mouse Model of Huntington’s Disease

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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.

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Acknowledgments

We would like to thank Mr. Steve Walters, Mrs. Dawn Sadler, Mrs. Karen Evans, and Dr. Verina Waights at the Open University for their excellent technical assistance and Drs Tony Hannan and Anton van Dellen of Oxford University for their help in establishing our R6/1 colony. We would also like to thank Professor Michael Levine and Mr Ehud Gruen for providing D2 knock-out mouse brains. This work was funded by the Open University Research Development Committee and the Royal Society.

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Author notes

  1. Austen J. Milnerwood

    Present address: Department of Neurology & Centre for Applied Neurogenetics, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2255, Wesbrook Mall, Vancouver, V6T 1Z3, Canada

  2. Damian M. Cummings

    Present address: University College London, Neuroscience, Physiology and Pharmacology, Gower Street, London, WC1E 6BT, UK

  3. Glenn M. Dallérac

    Present address: CIRB, CNRS UMR 7241, INSERM U1050, Collège de France, 75005, Paris, France

Authors and Affiliations

  1. Huntington’s Disease Research Forum, Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, MK76AA, UK

    Glenn M. Dallérac, Damian M. Cummings, Mark C. Hirst, Austen J. Milnerwood & Kerry P. S. J. Murphy

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  1. Glenn M. Dallérac
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  2. Damian M. Cummings
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Dallérac, G.M., Cummings, D.M., Hirst, M.C. et al. Changes in Dopamine Signalling Do Not Underlie Aberrant Hippocampal Plasticity in a Mouse Model of Huntington’s Disease. Neuromol Med 18, 146–153 (2016). https://doi.org/10.1007/s12017-016-8384-z

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