CONTROL OF NEURONAL EXCITABILITY BY AXONAL KCNQ CHANNELS AND IMPACT OF BFNC MUTATIONS: A COMPUTATIONAL MODELING STUDY
Abstract number :
2.013
Submission category :
Year :
2005
Submission ID :
5317
Source :
www.aesnet.org
Presentation date :
12/3/2005 12:00:00 AM
Published date :
Dec 2, 2005, 06:00 AM
Authors :
1Stephen D. Cranstoun, and 2Edward C. Cooper
Mutations in KCNQ2 and KCNQ3 result in benign familial neonatal convulsions (BFNC). Recently, Devaux et al. described the presence of these voltage-gated K+ channel subunits on unmyelinated portions of axons (nodes of Ranvier and axon initial segments, AIS) where action potentials are generated and propagated (JNeurosci 2004 24:1236). To better understand the how mutations in axonal KCNQ channels may contribute to the BFNC phenotype, we have developed a computational model containing axonal KCNQ channels. A morphologically realistic multicompartment CA1 pyramidal cell model, including dendrites, soma, and a myelinated axon, was assembled. Somatic and dendritic compartments contained voltage-gated Na+ and K+ channels at densities sufficient to propagate, but not initiate action potentials. Channel densities at nodes of Ranvier were based on voltage-clamp data from peripheral axons. Heteromeric KCNQ2/3 channels were inserted into the AIS at densities estimated from anatomical and nodal recording data. We determined the effects on neuronal firing properties, when AIS wildtype KCNQ2/3 channels were replaced by channels including a subunit with one of 8 different BFNC mutations. KCNQ channels at the AIS exerted a high degree of control over spike thresholds and firing frequencies in response to excitatory inputs. In simulated somatic voltage-clamp recordings, axonal KCNQ currents were detectable but exhibited markedly attenuated amplitudes. When channels containing BFNC mutant subunits were introduced at the AIS only, at densities based on results of heterologous expression studies, increased neuronal excitability was observed.[figure1] Because of their slow kinetics and activity in the subthreshold voltage range, a small number of KCNQ channels localized at the proximal axon can exert powerful control over neuronal output. Mutations that slightly reduce axonal KCNQ channel function may result in significant hyperexcitability. (Supported by NINDS R01 NS49119 and NICHD P30 HD26979 (ECC) and NSF-GSF, NIH T32-GM07517, NIH 1-R01-NS41811-03 and the Whitaker Foundation (SDC).)