Abstract
Epileptic seizures reflect enduring alterations in structure and function of the brain that support recurrent, spontaneous abnormal neuronal discharges and can lead to clinically overt changes in motor control, sensory perception, behavior, or autonomic function. At a cellular level, two hallmark features of epileptiform activity are neuronal hyperexcitability and neuronal hypersynchrony. It is important to understand that a single abnormally discharging neuron is insufficient to produce a clinical seizure. For a seizure to manifest electroclinically, there must be synchronous activity of large populations or networks of neurons (McCormick and Contreras, 2001). In this context, seizures can be considered emergent properties of neuronal networks, similar to the emergence of cognition (Faingold, 2004). Notwithstanding this important concept, determination of the mechanisms of action of antiepileptic drugs (AEDs) usually begins with, or is reduced to, modulation of membrane-bound ion channels. The neuronal cell membrane is populated by a variety of ion channels that convert chemical signals into electrical activity. As such, ion channels occupy an important position in neuronal excitability. Incoming signals act through ligand-gated and voltage-gated ion channels to generate excitatory or inhibitory responses, which may be subthreshold or suprathreshold for subsequent action potential initiation and which, in turn, give rise downstream to action-potential-propagated neurochemical signals. Traditionally, three major classes of molecular targets are believed to be relevant for limiting epileptic activity: (1) voltage-gated sodium and calcium channels, (2) γ-aminobutyric acid type A (GABAA) receptors, and (3) ionotropic glutamate receptors. Most clinically useful AEDs do modulate one or more of these targets, but, as will be presented later, many of the AEDs also affect additional molecular targets (Bialer et al., 2007; Meldrum and Rogawski, 2007; Rho and Sankar, 1999; Rogawski, 2006; White et al., 2007).