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The Journal of Neuroscience, December 7, 2005, 25(49):11455-11467; doi:10.1523/JNEUROSCI.3153-05.2005

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Cellular/Molecular
Modifying the Subunit Composition of TASK Channels Alters the Modulation of a Leak Conductance in Cerebellar Granule Neurons

M. Isabel Aller,¹ Emma L. Veale,³ Anni-Maija Linden,⁴ Cristina Sandu,¹ Markus Schwaninger,² Louisa J. Evans,³ Esa R. Korpi,⁴ Alistair Mathie,³ William Wisden,¹ and Stephen G. Brickley³

Departments of ¹Clinical Neurobiology and ²Neurology, University of Heidelberg, 69120 Heidelberg, Germany, ³Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom, and ⁴Institute of Biomedicine, Pharmacology, FI-00014 University of Helsinki, Helsinki, Finland

Two-pore domain potassium (K_2P) channel expression is believed to underlie the developmental emergence of a potassium leak conductance [I_K(SO)] in cerebellar granule neurons (CGNs), suggesting that K_2P function is an important determinant of the input conductance and resting membrane potential. To investigate the role that different K_2P channels may play in the regulation of CGN excitability, we generated a mouse lacking TASK-1, a K_2P channel known to have high expression levels in CGNs. In situ hybridization and real-time PCR studies in wild-type and TASK-1 knock-outs (KOs) demonstrated that the expression of other K_2P channels was unaltered in CGNs. TASK-1 knock-out mice were healthy and bred normally but exhibited compromised motor performance consistent with altered cerebellar function. Whole-cell recordings from adult cerebellar slice preparations revealed that the resting excitability of mature CGNs was no different in TASK-1 KO and littermate controls. However, the modulation of IK(SO) by extracellular Zn²⁺, ruthenium red, and H⁺ was altered. The I_K(SO) recorded from TASK-1 knock-out CGNs was no longer sensitive to alkalization and was blocked by Zn²⁺ and ruthenium red. These results suggest that a TASK-1-containing channel population has been replaced by a homodimeric TASK-3 population in the TASK-1 knock-out. These data directly demonstrate that TASK-1 channels contribute to the properties of I_K(SO) in adult CGNs. However, TASK channel subunit composition does not alter the resting excitability of CGNs but does influence sensitivity to endogenous modulators such as Zn²⁺ and H⁺.

Key words: potassium channels; cerebellum; motor control; patch-clamp; knock-out mice; excitability

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Received May 4, 2005; revised September 19, 2005; accepted October 20, 2005.

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