Cerebellar Pathophysiology in a Mouse Model of Spinocerebellar Ataxia
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1
Albert Einstein College of Medicine, United States
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2
University of Minnesota, United States
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3
Northwestern University, United States
Spinocerebellar ataxia type 8 (SCA8) is a movement disorder caused by a mutation in a noncoding RNA which is expected to perturb expression of Kelch-like 1 (Klhl1), a protein of yet unknown function. Previous work established that Purkinje cell-specific deletion of Klhl1 in mice recapitulates the motor symptoms observed in SCA8 patients, namely late-onset slowly progressive gait abnormalities and cerebellar atrophy. We took advantage of this mouse model of SCA8 to examine the pathophysiology of this disorder. In these mice the observed motor deficits are attributable to Purkinje cell dysfunction because the mice do not exhibit any cerebellar cell loss, and deletion of Klhl1 is restricted to Purkinje cells. The present work revealed two major defects in Purkinje cell function arising from deletion of Klhl1. Both in vivo and in vitro the mutant Purkinje cells exhibited an atypically lower and more erratic firing rate, which arose from a stronger GABAergic synaptic drive. This enhanced synaptic inhibition is likely a homeostatic network-level consequence to a Purkinje cell-specific dysfunction, namely a significant elevation in their intrinsic excitability observed in tandem. This aberrant excitability of knockout Purkinje cells can be accounted for by the changes in passive electrical properties of Purkinje cell dendrites. Our work aimed at understanding the etiology of SCA8 is an important advance toward identifying potential therapeutic targets of this debilitating condition.
Conference:
EMBO workshop: Gaba Signalling and Brain Networks , Amsterdam, Netherlands, 30 Jun - 2 Jul, 2010.
Presentation Type:
Poster Presentation
Topic:
Posters
Citation:
Dizon
M,
Khodakhah
K,
Koob
M,
Tara
E and
Walter
J
(2010). Cerebellar Pathophysiology in a Mouse Model of Spinocerebellar Ataxia.
Conference Abstract:
EMBO workshop: Gaba Signalling and Brain Networks .
doi: 10.3389/conf.fnins.2010.15.00006
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Received:
23 Jun 2010;
Published Online:
23 Jun 2010.
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Correspondence:
M. Dizon, Albert Einstein College of Medicine, New York, United States, MariaJohanna.Dizon@phd.einstein.yu.edu