Na_V1.1 channels and epilepsy

Abstract

Voltage-gated sodium channels initiate action potentials in brain neurons, and sodium channel blockers are used in therapy of epilepsy. Mutations in sodium channels are responsible for genetic epilepsy syndromes with a wide range of severity, and the Na V 1.1 channel encoded by the SCN1A gene is the most frequent target of mutations. Complete loss-of-function mutations in Na V 1.1 cause severe myoclonic epilepsy of infancy (SMEI or Dravet's Syndrome), which includes severe, intractable epilepsy and comorbidities of ataxia and cognitive impairment. Mice with loss-of-function mutations in Na V 1.1 channels have severely impaired sodium currents and action potential firing in hippocampal GABAergic inhibitory neurons without detectable effect on the excitatory pyramidal neurons, which would cause hyperexcitability and contribute to seizures in SMEI. Similarly, the sodium currents and action potential firing are also impaired in the GABAergic Purkinje neurons of the cerebellum, which is likely to contribute to ataxia. The imbalance between excitatory and inhibitory transmission in these mice can be partially corrected by compensatory loss-of-function mutations of Na V 1.6 channels, and thermally induced seizures in these mice can be prevented by drug combinations that enhance GABAergic neurotransmission. Generalized epilepsy with febrile seizures plus (GEFS + ) is caused by missense mutations in Na V 1.1 channels, which have variable biophysical effects on sodium channels expressed in non-neuronal cells, but may primarily cause loss of function when expressed in mice. Familial febrile seizures is caused by mild loss-of-function mutations in Na V 1.1 channels; mutations in these channels are implicated in febrile seizures associated with vaccination; and impaired alternative splicing of the mRNA encoding these channels may also predispose some children to febrile seizures. We propose a unified loss-of-function hypothesis for the spectrum of epilepsy syndromes caused by genetic changes in Na V 1.1 channels, in which mild impairment predisposes to febrile seizures, intermediate impairment leads to GEFS + epilepsy, and severe or complete loss of function leads to the intractable seizures and comorbidities of SMEI.

“Untangling” Alzheimer's Disease and Epilepsy

“…Another study found that APP mice had a deficit in Nav1.1 expression primarily in a subset of fast-spiking GABAergic interneurons that express parvalbumin (46). Wholecell recordings from the interneurons showed that there were defects in action potential firing (46), similar to studies of mice with SCN1A mutations (44). In both the APP and SCN1A mice, seizures can potentially be explained by disinhibition of principal cells, innervated by interneurons that do not release adequate GABA.…”

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

“…However, most Nav1.1 mutations have their ultimate epileptogenic effects by reducing Nav1.1-mediated whole cell sodium currents in GABAergic neurons, resulting in widespread loss of brain inhibition, an ideal background for the genesis of epileptic seizures (for review: Catterall et al 2010, Ragsdale 2008). …”

Epigenetic Mechanisms in Stroke and Epilepsy

“…Epilepsy can also arise as a consequence of spontaneous or inherited gene mutations. Interestingly, the latter includes a vast number of channelopathies, in which recurrent seizures arise from single-point mutations, deletions, duplications, or expansions in genes encoding a component of a voltage-or ligand-gated ion channels, but also many other genes that directly or indirectly control brain development and neuronal function and activity (Catterall et al, 2008(Catterall et al, , 2010Galanopoulou et al, 2012).…”