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Dallerac, G.M.; Levasseur, G.; Vatsavayai, S.C.; Milnerwood, A.J.; Cummings, D.M.; Kraev, I.; Huetz, C.; Evans, K.A.; Walters, S.W.; Rezaie, P.; Cho, Y.; Hirst, M.C. and Murphy, K.P.S.J.
(2015).
DOI: https://doi.org/10.1159/000375126
Abstract
<b>Background:<b/><br> 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.</br> <b>Objective:<b/><b> In the present study, we examined the properties of midbrain dopaminergic neurones and dopamine release in presymptomatic and symptomatic transgenic HD mice. Methods and 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 (KC<sub>a</sub>2.3 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.</br> <b>Conclusions:<b/><b> 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.</br>
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)
