Abstract
Episodic ataxia type-2 (EA2) is caused by mutations in P/Q-type voltage-gated calcium channels that are expressed at high densities in cerebellar Purkinje cells. Because P/Q channels support neurotransmitter release at many synapses, it is believed that ataxia is caused by impaired synaptic transmission. Here we show that in ataxic P/Q channel mutant mice, the precision of Purkinje cell pacemaking is lost such that there is a significant degradation of the synaptic information encoded in their activity. The irregular pacemaking is caused by reduced activation of calcium-activated potassium (Kca) channels and was reversed by pharmacologically increasing their activity with 1-ethyl-2-benzimidazolinone (EBIO). Moreover, chronic in vivo perfusion of EBIO into the cerebellum of ataxic mice significantly improved motor performance. Our data support the hypothesis that the precision of intrinsic pacemaking in Purkinje cells is essential for motor coordination and suggest that KCa channels may constitute a potential therapeutic target in EA2.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 389-397 |
| Number of pages | 9 |
| Journal | Nature Neuroscience |
| Volume | 9 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2006 |
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ASJC Scopus subject areas
- Neuroscience(all)
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Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. / Walter, Joy T.; Alviña, Karina; Womack, Mary D.; Chevez, Carolyn; Khodakhah, Kamran.
In: Nature Neuroscience, Vol. 9, No. 3, 03.2006, p. 389-397.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia
AU - Walter, Joy T.
AU - Alviña, Karina
AU - Womack, Mary D.
AU - Chevez, Carolyn
AU - Khodakhah, Kamran
PY - 2006/3
Y1 - 2006/3
N2 - Episodic ataxia type-2 (EA2) is caused by mutations in P/Q-type voltage-gated calcium channels that are expressed at high densities in cerebellar Purkinje cells. Because P/Q channels support neurotransmitter release at many synapses, it is believed that ataxia is caused by impaired synaptic transmission. Here we show that in ataxic P/Q channel mutant mice, the precision of Purkinje cell pacemaking is lost such that there is a significant degradation of the synaptic information encoded in their activity. The irregular pacemaking is caused by reduced activation of calcium-activated potassium (Kca) channels and was reversed by pharmacologically increasing their activity with 1-ethyl-2-benzimidazolinone (EBIO). Moreover, chronic in vivo perfusion of EBIO into the cerebellum of ataxic mice significantly improved motor performance. Our data support the hypothesis that the precision of intrinsic pacemaking in Purkinje cells is essential for motor coordination and suggest that KCa channels may constitute a potential therapeutic target in EA2.
AB - Episodic ataxia type-2 (EA2) is caused by mutations in P/Q-type voltage-gated calcium channels that are expressed at high densities in cerebellar Purkinje cells. Because P/Q channels support neurotransmitter release at many synapses, it is believed that ataxia is caused by impaired synaptic transmission. Here we show that in ataxic P/Q channel mutant mice, the precision of Purkinje cell pacemaking is lost such that there is a significant degradation of the synaptic information encoded in their activity. The irregular pacemaking is caused by reduced activation of calcium-activated potassium (Kca) channels and was reversed by pharmacologically increasing their activity with 1-ethyl-2-benzimidazolinone (EBIO). Moreover, chronic in vivo perfusion of EBIO into the cerebellum of ataxic mice significantly improved motor performance. Our data support the hypothesis that the precision of intrinsic pacemaking in Purkinje cells is essential for motor coordination and suggest that KCa channels may constitute a potential therapeutic target in EA2.
UR - http://www.scopus.com/inward/record.url?scp=33344454896&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33344454896&partnerID=8YFLogxK
U2 - 10.1038/nn1648
DO - 10.1038/nn1648
M3 - Article
C2 - 16474392
AN - SCOPUS:33344454896
VL - 9
SP - 389
EP - 397
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 3
ER -