Transcriptional Upregulation of Ca_v3.2 Mediates Epileptogenesis in the Pilocarpine Model of Epilepsy

Abstract

In both humans and animals, an insult to the brain can lead, after a variable latent period, to the appearance of spontaneous epileptic seizures that persist for life. The underlying processes, collectively referred to as epileptogenesis, include multiple structural and functional neuronal alterations. We have identified the T-type Ca 2ϩ channel Ca v 3.2 as a central player in epileptogenesis. We show that a transient and selective upregulation of Ca v 3.2 subunits on the mRNA and protein levels after status epilepticus causes an increase in cellular T-type Ca 2ϩ currents and a transitional increase in intrinsic burst firing. These functional changes are absent in mice lacking Ca v 3.2 subunits. Intriguingly, the development of neuropathological hallmarks of chronic epilepsy, such as subfield-specific neuron loss in the hippocampal formation and mossy fiber sprouting, was virtually completely absent in Ca v 3.2 Ϫ/Ϫ mice. In addition, the appearance of spontaneous seizures was dramatically reduced in these mice. Together, these data establish transcriptional induction of Ca v 3.2 as a critical step in epileptogenesis and neuronal vulnerability.

The Presynaptic Active Zone Protein RIM1α Controls Epileptogenesis following Status Epilepticus

“…This dose of pilocarpine was chosen because it reliably induces status epilepticus in wild-type animals while keeping mortality as low as possible. Seizures were classified as described by Pitsch et al (2007) and Becker et al (2008), i.e., stage III (severe seizures with rearing without falling) and stage IV (severe seizures with rearing and falling/loss of righting ability). Continuous tonic-clonic seizures (status epilepticus) were classified as stage V. Of the pilocarpine-injected animals, only those that developed SE (SE-experienced) were used for further EEG analysis, electrophysiological in vitro and in vivo examinations, and histological analyses.…”

“…The electrographic features of SE and chronic seizures were analyzed with a telemetric EEG/video-monitoring system. The telemetric system (Data Science International), implantation procedure, and postoperative treatment were previously described in detail (Pitsch et al, 2007;Becker et al, 2008). To examine the features of SE, mice were implanted with EEG electrodes 7 d before induction of SE.…”

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

“…Knowing that ethosuximide is a relatively selective inhibitor of T-type Ca 2+ channels it is intriguing to speculate that the effect on T-type Ca 2+ channels could be responsible. Indeed, T-type Ca 2+ channels seem to play a critical role in the epileptogenic process in the mouse pilocarpine SE model [34]. In this model, increased T-type Ca 2+ current and intrinsic burst firing in hippocampal CA1 pyramidal neurons was associated with later spontaneous seizure expression.…”

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

“…Increase in intrinsic excitability (47), selective excitatory synaptogenesis (48), and reduction in inhibitory transmission (14) were all reported to occur during epileptogenesis. Our recordings from neocortical pyramidal neurons indicate activity-dependent increase in excitability that does not require a prominent change in intrinsic properties and/or spontaneous synaptic transmission, and is probably astrocyte mediated (10).…”