The Sodium Channel and Morbidities Associated with Dravet Syndrome (SMEI)
A focus of the works of Dr. Louis Cooper, Chair of Pharmacology, University of Washington School of Medicine
Written by : Harriet Davies, PharmD
Dr. Cooper is interested in electrical signaling in the brain and peripheral nervous system, its regulation in normal physiology, and its dysfunction in disease. His work focuses on the sodium channels that initiate action potentials and the calcium channels that initiate synaptic transmission in neurons and excitation-contraction coupling in muscle. Cooper and his group use a combination of molecular biology, mouse genetics, biochemistry, structural biology, electrophysiology, and confocal immunocytochemistry.
One current research project focuses on severe myoclonic epilepsy of infancy, an autosomal dominant genetic epileptic encephalopathy with devastating consequences for affected children, which is caused by heterozygous loss-of-function mutations in the gene encoding the brain sodium channel Nav1.1. He has developed a mouse genetic model that recapitulates all of the features of this disease, including the pattern and severity of seizures and the co-morbidities. With this mouse model, he has shown that the primary pathogenic event in this disease is failure of action potential generation in GABAergic inhibitory neurons. This impairment disinhibits the excitatory neurons and causes uncontrolled hyperexcitability and epilepsy, as well as ataxia, sleep disturbance and other co-morbidities. Cooper expects that findings from this investigation will provide crucial new information on the cell biology and regulation of sodium channels in this disease model, define the molecular and cellular mechanisms underlying severe myoclonic epilepsy in infancy, and yield insights into novel pharmacotherapies that may be effective in this intractable childhood disease.
Dr. Cooper’s UW Pharmacology web page
We are learning more about the morbidities associated with Dravet Syndrome as more patients are diagnosed with the disorder; however, the complex cellular mechanisms involved are not fully understood. Recent discoveries by Bill Cooper, PhD and colleagues at the University of Washington bring us a step closer to understanding the physiochemical mechanisms associated with genetically distinct epilepsy syndromes involving the sodium channel.
Sodium channels are critical regulators of neuronal excitability. De novo loss of function mutations in the SCN1A potentially lead to haploinsufficiency of Nav1.1 channels. Theoretically, haploinsufficiency of the Nav1.1 channel should not cause epilepsy because reduced sodium current produces neuronal inexcitability rather than hyperexcitability that is associated with seizure activity.
Dr. Cooper has generated mouse models of Dravet Syndrome by ablating the SCN1A gene in mice and has shown that dramatic loss of sodium current in the hippocampal GABAergic inhibitory neurons in these mice may cause their epilepsy. Upregulation, which is a protective mechanism that allows more neurons to be generated during a loss, is not sufficient to produce enough GABAergic inhibitory neurotransmission to balance the naturally existing excitatory neurotransmittors; therefore, seizures ensue. The results of these mouse models suggest that failure of excitability of hippocampal GABAergic inhibitory neurons is a possible cause of this intractable epilepsy syndrome. The theory is consistent with the response seen in children with Dravet Syndrome to benzodiazepines, including clobazam, clonazepam. diazepam, midazolam, et al. and other antiepileptic drugs that work on GABA receptors in the brain to enhance inhibitory neurotransmission.
Dr. Cooper found that mice with a heterozygous loss of one allele of the Nav1.1 channel gene are ataxic, as measured in tests of walking a straight line and walking on a narrow rod. Analysis of the cerebellar Purkinje neurons, which are crucial in coordinating movement, show that there is a dramatic loss of sodium current. The Purkinje neurons are the projection neurons of the cerebellum, sending crucial information on coordination of complex movements to deep cerebellar nuclei and from there onwards to the cerebral cortex and other higher centers. Loss of excitability of these neurons is sufficient to cause profound ataxia.
The Purkinje neurons are unique because they are GABAergic inhibitory neurons that serve as projection neurons, in contrast to virtually all other projection neurons, which are excitatory. Dr. Cooper’s team believes that the dramatic loss of sodium current in both the hippocampal inhibitory GABAergic interneurons and the cerebellar inhibitory Purkinje neurons means that many classes of GABAergic neurons throughout the brain may have reduced sodium currents and reduced excitability, and that impaired excitability of these other inhibitory neurons may be responsible for other aspects of the disease like spasticity and cognitive impairment. They are beginning to design experiments to test these ideas.
Dr. CoCatterall lab is looking for comparable deficits to humans with Dravet syndrome in SMEI mouse models, and then using the mouse model to try to uncover the reason for the deficit. There is hope that this research brings us a step closer to figuring out the physiochemical aspects of Dravet Syndrome and will allow for designing drugs and exploring other treatment options consistent with associated neurochemical imbalances.
References:
Yu FH, Masimo M, Westenbroek RE et al. Reduced sodium current in GABAergic interneurons in a mouse model of Severe Myoclonic Epilepsy of Infancy. Nature Neuroscience 9(9);Sept 2006:1142-49.
Personal correspondence with Dr. CoBill Catterallegarding pending publications.