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Pathogenic mechanisms
B24 Dysfunctional dopaminergic neurones and biphasic activity-dependent dopamine release in mouse models of Huntington's disease
  1. KPSJ Murphy,
  2. GM Dallerac,
  3. AJ Milnerwood,
  4. DM Cummings,
  5. SC Vatsavayai,
  6. A Stramek,
  7. KA Evans,
  8. SW Walters,
  9. MC Hirst
  1. Huntington's Disease Research Forum, Department of Life, Health & Chemical Sciences, Milton Keynes, UK

Abstract

Background There is growing evidence that the earliest symptoms of Huntington's disease (HD) are attributable to abnormalities in synaptic and cell function. The advent of predictive gene testing combined with PET imaging has revealed an early loss of dopamine receptors in asymptomatic gene carriers. We have previously shown that cortical synaptic plasticity is abnormal in HD mice and can be rescued by dopaminergic therapy (Cummings et al (2006) Human Molecular Genetics; Dallerac et al (2011) Neurodegen. Dis.).

Aim To assess the electrophysiological properties of mid-brain dopaminergic neurons and their ability to release dopamine in 89Q (preclinical; Vatsavayai et al (2007) Brain Res. Bull.) and 116Q (symptomatic) R6/1 mice.

Methods Brain slices were prepared from 89Q and 116Q R6/1 mice and controls aged 9–11 months. Intracellular recordings were made from dopaminergic neurons located in the substantia nigra. Evoked release of striatal dopamine was measured using amperometry.

Results Resting membrane potentials and input resistances were normal, however 116Q and 89Q tg dopaminergic neurones exhibited a statistically significant decrease in the amplitude and duration of the slow after hyperpolarisation and a marked increase in firing rate upon depolarisation. Evoked dopamine release was dramatically reduced in 116Q slices compared with controls. Unexpectedly, the converse was found for slices prepared from 89Q mice. Maximal dopamine release in these slices was significantly greater than controls.

Conclusions These data suggest that (i) dopaminergic neurons are abnormal and (ii) activity-dependent dopamine release undergoes a temporal biphasic shift from a supra level of release to an abnormally low one; a profile that may underlie and contribute to the pathogenic and symptomatic complexity of HD. Collectively, our findings suggest that the dopamine system may represent a site for intervention in the early pathogenesis of HD.

  • Dopamine
  • substantia nigra
  • electrophysiology

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