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Commentary Childhood absence epilepsy (CAE) accounts for 2 to 10 percent of all epileptic disorders in children. It involves short lapses of consciousness that are highly disruptive for learning and other activities of daily life. In the 1950s, Zimmerman and Burgemeister set out to find novel medications to treat CAE that would be as effective as trimethadione, but with fewer side effects (1). They discovered that among the candidates, ethosuximide had the highest effectiveness against CAE and lowest undesirable side effects. This drug remains the first-choice medication for CAE. One of the generally agreed mechanisms for the effect of ethosuximide is blockade of T-type voltage gated calcium channels, i.e. those in the Cav3 family (2). The three members of the Cav3 family — Cav3.1, 3.2, and 3.3 — are differentially expressed in various brain regions (3). Studies using knockout models of Cav3.1 and Cav3.3 have documented that these channels are indispensable for burst firing. This is consistent with their ability to open with small depolarization of membrane potential and subsequently promote generation of low-threshold calcium spikes (4, 5). Burst firing has been shown to be a highly reliable method of driving activity in downstream neurons (6), suggesting T-type calcium channels, along with other means of generating bursts, play critical roles in normal information processing. In pathological conditions, mutations of these channels have been hypothesized to lead to greater calcium influx near resting membrane potential, and enhanced burst firing that would increase the propensity to develop epileptic seizures. Indeed, genetic alterations of CACNA1H (the gene encoding Cav3.2) have been identified in many cases of CAE and also in patients with other forms of idiopathic generalized epilepsy, suggesting that CACNA1H is a susceptibility gene for epileptic disorders (7, 8). It is unknown, however, whether Cav3.2 actually affects the firing property of neurons and how mutations of Cav3.2 protein could lead to different types of epilepsy. In this comprehensive study published in Genes and Development, Wang et al. addressed these questions by using an elegant combination of complementary approaches, ranging from genetic manipulation of neurons in vivo or in culture, T-channel specific pharmacology, electrophysiology, calcium imaging, and pathway-specific optogenetic stimulation, as well as ultrastructural studies utilizing immunogold-electron microscopy. In contrast to previous findings that Cav3 channels modulate neuronal excitability through boosting intrinsic excitability by stimulating burst firing (4), the authors demonstrated that overexpression of Cav3.2 — with either gain-offunction mutation linked to CAE-linked hCav3.2 (C456S) or the wild-type form, surprisingly had no effect on GABA-ergic responses, paired-pulse facilitation, membrane potential, bursting activity or spiking frequency. These results differ from those in a recent study in cultured neurons showing CaV3.2 Calcium Channels Control NMDA Receptor-Mediated Transmission: A New Mechanism for Absence Epilepsy.

Criminal Minds: Cav3.2 Channels Are the Culprits, but NMDAR Are the Co-Conspirators