Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice
Article first published online: 5 DEC 2012
© 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society
The Journal of Physiology
Volume 591, Issue 1, pages 241–255, January 2013
How to Cite
Sun, W., Wagnon, J. L., Mahaffey, C. L., Briese, M., Ule, J. and Frankel, W. N. (2013), Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice. The Journal of Physiology, 591: 241–255. doi: 10.1113/jphysiol.2012.240168
- Issue published online: 7 JAN 2013
- Article first published online: 5 DEC 2012
- Accepted manuscript online: 2 NOV 2012 09:15AM EST
- (Received 2 July 2012; accepted after revision 22 October 2012; first published online 22 October 2012)
- • Inappropriate electrochemical signalling between neurons is a central problem in epilepsy. Only a fraction of all heritable epilepsies are solved, and many are due to ion channel mutations.
- • Ion channels are cell surface molecules that initiate and coordinate electrochemical signalling, by allowing the right combination of ions to flow in and out of a neuron.
- • Ion channels may be regulated by other genes. We recently determined that the RNA-binding protein, ‘CELF4’, affects expression of many molecules, including ion channels, to coordinate electrochemical signalling.
- • Here we conclude that a sodium channel called Nav1.6 is the primary instigator of abnormal excitation when CELF4 is impaired.
- • Nav1.6 expression is increased in the axon initial segment – a part of the neuron that initiates electrical activity – altering intrinsic excitability. We surmise that in a brain that already has difficulty regulating other molecules due to CELF4 deficiency, this leads to uncontrolled network excitation and seizures.
Abstract Mice deficient for CELF4, a neuronal RNA-binding protein, have a complex seizure disorder that includes both convulsive and non-convulsive seizures, and is dependent upon Celf4 gene dosage and mouse strain background. It was previously shown that Celf4 is expressed predominantly in excitatory neurons, and that deficiency results in abnormal excitatory synaptic neurotransmission. To examine the physiological and molecular basis of this, we studied Celf4-deficient neurons in brain slices. Assessment of intrinsic properties of layer V cortical pyramidal neurons showed that neurons from mutant heterozygotes and homozygotes have a lower action potential (AP) initiation threshold and a larger AP gain when compared with wild-type neurons. Celf4 mutant neurons also demonstrate an increase in persistent sodium current (INaP) and a hyperpolarizing shift in the voltage dependence of activation. As part of a related study, we find that CELF4 directly binds Scn8a mRNA, encoding sodium channel Nav1.6, the primary instigator of AP at the axon initial segment (AIS) and the main carrier of INaP. In the present study we find that CELF4 deficiency results in a dramatic elevation in the expression of Nav1.6 protein at the AIS in both null and heterozygous neurons. Together these results suggest that activation of Nav1.6 plays a crucial role in seizure generation in this complex model of neurological disease.