The goal of the proposed research is to take a biophysical approach to understand how antiepileptic drugs targeted to voltage-dependent sodium channels regulate neuronal firing by differentially binding to different gating states of the channels. The work brings together two lines of research in the laboratory, one characterizing the state-dependent interaction of drugs like lidocaine, phenytoin, carbamazepine, and lacosamide with sodium channels and the other exploring how gating of sodium channels regulates firing of a variety of mammalian central neurons. A key property of antiepileptic drugs is differential binding to different gating states of sodium channels, but how this changes firing of particular kinds of central neurons to control pathological neuronal activity is poorly understood. For example, higher affinity binding to open and inactivated states results in use-dependence, with increased inhibition as channels cycle through open and inactivated states during action potentials. Yet, this does not easily explain their clinical action, because use-dependence might predict more potent inhibition of GABAergic inhibitory neurons, which typically fire at high frequencies, than glutamatergic excitatory neurons, which typically fire more slowly. We will examine how antiepileptic drugs interact with the gating of neuronal sodium channels and explore how state-dependent binding and unbinding regulates the firing patterns of a variety of excitatory and inhibitory neurons. We will follow up preliminary data showing that carbamazepine, phenytoin, and lamotrigine are all more effective in inhibiting firing of slower-firing glutamatergic pyramidal neurons than fast-spiking GABAergic neurons. We will analyze how these drugs and others (including the new anti- epileptic cannabidiol and a novel, more potent carbamazepine derivative) interact with gating of both native and cloned sodium channels and how the resulting changes in sodium current modify the firing patterns of a variety of excitatory and inhibitory neurons in a manner depending on the repertoire of other channels. The experimental design will combine recordings of action potential firing with voltage-clamp analysis of the underlying sodium currents, using intact neurons in brain slice, acutely dissociated neurons, and heterologously expressed cloned channels. A key feature will be to study action potential firing, channel gating kinetics, and drug action at 37 C.

Public Health Relevance

The goal of this work is to understand how antiepileptic agents modify the gating of sodium channels and thereby differentially modify firing of different kinds of central neurons. An understanding of how state- dependent binding and unbinding of antiepileptic drugs to sodium channels regulates firing of different kinds of neurons can lead to ideas of how to better inhibit pathological activity while minimizing effects on normal activity.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
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Silberberg, Shai D
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Harvard Medical School
Schools of Medicine
United States
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