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Open Access Publications from the University of California


The Department of Neurology, University of California, Davis is composed of a diverse faculty engaged in research on neurological disorders and fundamental neuroscience. Areas of strength in the department are in neurological therapeutics, epilepsy, cognitive neuroscience, dementias, neuromuscular disorders, Huntington's disease and multiple sclerosis.

Faculty in the Department of Neurology are situated on the UC Davis medical campus in Sacramento (in the Lawrence J. Ellison Ambulatory Care Center and at the M.I.N.D. Institute); at the UC Davis Center for Neuroscience and at the Center for Mind and Brain in Davis; and at the Department of Veterans Affairs Northern California Health Care System in Martinez.

Michael A. Rogawski, Chair
University of California, Davis
4860 Y Street, Suite 3700
Sacramento CA 95817

Department of Neurology, UC Davis School of Medicine

There are 5 publications in this collection, published between 2003 and 2008.
Recent Work (5)

Epilepsy-Associated Dysfunction in the Voltage-Gated Neuronal Sodium Channel SCN1A

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel subunit (NaV1.1) are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. One previously reported GEFS+ mutation (I1656M) and an additional novel allele (R1657C), both affecting residues in a voltage-sensing S4 segment, exhibited a similar depolarizing shift in the voltage dependence of activation. Additionally, R1657C showed a 50% reduction in current density and accelerated recovery from slow inactivation. Unlike three other GEFS+ alleles that we recently characterized, neither R1657C nor I1656M gave rise to a persistent, noninactivating current. In contrast, two other GEFS+ mutations (A1685V and V1353L) and L986F, an SMEI-associated allele, exhibited complete loss of function. In conclusion, our data provide evidence for a wide spectrum of sodium channel dysfunction in familial epilepsy and demonstrate that both GEFS+ and SMEI can be associated with nonfunctional SCN1A alleles.

What Clinical Observations on the Epidemiology of Antiepileptic Drug Intractability Tell Us About the Mechanisms of Pharmacoresistance

In the past several years, there have been important advances in the clinical epidemiology of antiepileptic drug resistance, as reviewed by Mohanraj and Brodie. It would appear that by and large, intractability is independent of the choice of antiepileptic drug (AED). Many patients will become seizure free on the first agent tried, irrespective of which one their physician decides to pick. Nonresponders to the first drug are in a different category: it is likely that they will continue to have seizures no matter which medicine or combination of medicines is tried. This simple clinical observation puts important constraints on the possible biological mechanisms for pharmacoresistance. In this essay, I consider the implications of the new clinical research for studies on the neurobiological mechanisms of AED intractability.

New Molecular Targets for Antiepileptic Drugs: alpha2delta, SV2A and Kv7/KCNQ/M Potassium Channels

Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on -aminobutyric acid–mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: 2, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development); and Kv7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves as the target for the investigational AEDs retigabine and ICA-105665. Functionally, all of the new targets modulate neurotransmitter output at synapses, focusing attention on presynaptic terminals as critical sites of action for AEDs.

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