R U OK? the Novel Therapeutic Potential of R Channels in Epilepsy

Commentary Absence epilepsy—the most common form of childhood epileptic disorders—is characterized by a brief and frequent loss of consciousness associated with generalized spike-and-wave discharges (1). These discharges represent synchronized oscillations in the corticothalamic system in which the thalamus is proposed to be an essential rhythm generator (2), although the role of the thalamus versus the cortex in absence seizure initiation remains controversial (3–5). The corticothalamic system is composed of reciprocally connected excitatory thalamocortical and corticothalamic pathways along with a key intervening structure, the reticular thalamus (RT). Both sets of long-range excitatory projections—the cortical and thalamocortical glutamatergic axons—emit axon collateral branches en route to their final targets to activate the GABAergic neurons within the RT. This leads to burst firing of RT cells and powerful inhibitory output to thalamocortical relay neurons, which paradoxically leads to reentrant circuit activation through postinhibitory burst firing. Oscillations are thought to arise and be sustained in the thalamocortical network through cyclical excitation, which is phased by the inhibitory output of RT. Thus a key element in generation of neural oscillations in thalamocortical circuits is the oscillatory burst activity in RT neurons, which is critical for the expression of spike-and-wave discharges (6). Therefore, the mechanisms underlying the bursting activity in this nucleus are of paramount importance. In particular, T-type calcium currents are thought to underlie the low-threshold calcium burst firing mode. Indeed, T currents and the bursts are reduced by ethosuximide (7, 8), which is a first choice anti-absence therapy (9). In 1993, Soong et al. reported the cloning of a T-type voltage-gated calcium channel: “rbE-II channel” (10). This channel ultimately turned out to be the R-type channel (Cav2.3) (11), and distinct from the “classic” T-type channel mediated by Cav3 channel family (12). In a recent study, Zaman et al. provided the first compelling evidence that the R current does act as a T-type calcium current in that it strongly contributes to the calcium-dependent burst firing mode in the RT neurons and to absence epilepsy. R channels are densely expressed in the cortex and RT but not in thalamocortical neurons. Although R channels are structurally related to high-voltage-activated calcium channels, some of their electrophysiological properties are closer to those of T channels (10), yet their activation threshold is ~25 mV more depolarized (11). Given the differences in their biophysical properties, T channels are more suitable for supporting slow pacemaker activity such as postinhibitory rebound, whereas R channels do provide more rapid, transient surges of calcium (11). While the role of T current in bursting of RT cells has been extensively studied, the involvement of R channels in this activity remained obscure. Zaman et al. examined this issue using Cav2.3 −/− mice. The investigators demonstrate for the first time that R channels play a major role in both supporting the burst firing mode in RT neurons and in experimental absence epilepsy. Using the state-of-art electrophysiological patch clamp techniques from brain slice preparations, Zaman et al. show that in wild-type RT cells postinhibitory rebound activation of T channels leads to depolarization and recruitment of R channels with a resultant Cav2.3 Channels Are Critical for Oscillatory Burst Discharges in the Reticular Thalamus and Absence Epilepsy.