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J Physiol Volume 586, Number 6, 1565-1579, March 15, 2008 DOI: 10.1113/jphysiol.2007.146597
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NEUROSCIENCE

Electrical remodelling maintains firing properties in cortical pyramidal neurons lacking KCND2-encoded A-type K+ currents

 Jeanne M. Nerbonne1, Benjamin R. Gerber1, Aaron Norris1 and Andreas Burkhalter2

1 Departments of Molecular Biology and Pharmacology
2 Anatomy and Neurobiology, Washington University Medical School, St Louis, MO 63110, USA

Considerable experimental evidence has accumulated demonstrating a role for voltage-gated K+ (Kv) channel pore-forming ({alpha}) subunits of the Kv4 subfamily in the generation of fast transient outward K+, IA, channels. Immunohistochemical data suggest that IA channels in hippocampal and cortical pyramidal neurons reflect the expression of homomeric Kv4.2 channels. The experiments here were designed to define directly the role of Kv4.2 in the generation of IA in cortical pyramidal neurons and to determine the functional consequences of the targeted deletion of Kv4.2 on the resting and active membrane properties of these cells. Whole-cell voltage-clamp recordings, obtained from visual cortical pyramidal neurons isolated from mice in which the KCND2 (Kv4.2) locus was disrupted (Kv4.2-/- mice), revealed that IA is indeed eliminated. In addition, the densities of other Kv current components, specifically IK and Iss, are increased significantly (P < 0.001) in most (~80%) Kv4.2-/- cells. The deletion of KCND2 (Kv4.2) and the elimination of IA is also accompanied by the loss of the Kv4 channel accessory protein KChIP3, suggesting that in the absence of Kv4.2, the KChIP3 protein is targeted for degradation. The expression levels of several Kv {alpha} subunits (Kv4.3, Kv1.4, Kv2.1, Kv2.2), however, are not measurably altered in Kv4.2-/- cortices. Although IA is eliminated in Kv4.2-/- pyramidal neurons, the mean ± S.E.M. current threshold for action potential generation and the waveforms of action potentials are indistinguishable from those recorded from wild-type cells. Repetitive firing is also maintained in Kv4.2-/- cortical pyramidal neurons, suggesting that the increased densities of IK and Iss compensate for the in vivo loss of IA.

(Received 17 October 2007; accepted after revision 8 January 2008; first published online 10 January 2008)
Corresponding author J. M. Nerbonne: Department of Molecular Biology and Pharmacology, Box 8103, Washington University Medical School, 660 South Euclid Avenue, St Louis, MO 63110-1093, USA. Email: jnerbonne{at}wustl.edu


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