title: Dysfunctional Dopaminergic Neurones in Mouse Models of Huntington's Disease: A Role for SK3 Channels.
abstract: BACKGROUND
  Huntington's disease (HD) is a late-onset fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the gene coding for the protein huntingtin and is characterised by progressive motor, psychiatric and cognitive decline. We previously demonstrated that normal synaptic function in HD could be restored by application of dopamine receptor agonists, suggesting that changes in the release or bioavailability of dopamine may be a contributing factor to the disease process.
  
  
  OBJECTIVE
  In the present study, we examined the properties of midbrain dopaminergic neurones and dopamine release in presymptomatic and symptomatic transgenic HD mice.
  
  
  RESULTS
  Using intracellular sharp recordings and immunohistochemistry, we found that neuronal excitability was increased due to a loss of slow afterhyperpolarisation and that these changes were related to an apparent functional loss and abnormal distribution of SK3 channels (KCa2.3 encoded by the KCNN3 gene), a class of small-conductance calcium-activated potassium channels. Electrochemical detection of dopamine showed that this observation was associated with an enhanced dopamine release in presymptomatic transgenic mice and a drastic reduction in symptomatic animals. These changes occurred in the context of a progressive expansion in the CAG repeat number and nuclear localisation of mutant protein within the substantia nigra pars compacta.
  
  
  CONCLUSIONS
  Dopaminergic neuronal dysfunction is a key early event in HD disease progression. The initial increase in dopamine release appears to be related to a loss of SK3 channel function, a protein containing a polyglutamine tract. Implications for polyglutamine-mediated sequestration of SK3 channels, dopamine-associated DNA damage and CAG expansion are discussed in the context of HD.
authors: Huntington's Disease Research Forum, Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, UK.
authors: Glenn M
authors: GM
authors: Dallérac
authors: Grégoire
authors: G
authors: Levasseur
authors: Sarat C
authors: SC
authors: Vatsavayai
authors: Austen J
authors: AJ
authors: Milnerwood
authors: Damian M
authors: DM
authors: Cummings
authors: Igor
authors: I
authors: Kraev
authors: Chloé
authors: C
authors: Huetz
authors: Karen A
authors: KA
authors: Evans
authors: Steve W
authors: SW
authors: Walters
authors: Payam
authors: P
authors: Rezaie
authors: Yoon
authors: Y
authors: Cho
authors: Mark C
authors: MC
authors: Hirst
authors: Kerry P S J
authors: KP
authors: Murphy
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena / Q000235:genetics; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology*; D004558:Electric Stimulation; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; C496900:Kcnn3 protein, mouse; D009419:Nerve Tissue Proteins; D051640:Small-Conductance Calcium-Activated Potassium Channels; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine