Altered Seizure Susceptibility in Mice Lacking the Ca(v)2.3 E-type Ca2+ Channel

Purpose: Recently the Ca(v)2.3 (E/R-type) voltage-gated calcium channel (VGCC) has turned out to be not only a potential target for different antiepileptic drugs (e.g., lamotrigine, topiramate) but also a crucial component in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and epileptiform activity in CA1 neurons. The aim of our study was to perform an electroencephalographic analysis, seizure-susceptibility testing, and histomorphologic characterization of Ca(v)2.3-/- mice to unravel the functional relevance of Ca(v)2.3 in ictogenesis.

Methods: Generalized and brain-specific Ca(v)2.3 knockout animals were analyzed for spontaneous epileptiform discharges by using both electrocorticographic and deep intracerebral recordings. In addition, convulsive seizure activity was induced by systemic administration of either 4-aminopyridine (4-AP; 10 mg/kg, i.p.) or pentylenetetrazol (PTZ; 80 mg/kg, s.c.) to reveal possible alterations in seizure susceptibility. Besides histomorphologic analysis, expression studies of other voltage-gated Ca2+ channels in Ca(v)2.3-/- brains were carried out by using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR).

Results: Both electrocorticographic and deep intrahippocampal recordings exhibited no spontaneous epileptiform discharges indicative of convulsive or nonconvulsive seizure activity during long-term observation. Gross histology and expression levels of other voltage-gated Ca2+ channels remained unchanged in various brain regions. Surprisingly, PTZ-induced seizure susceptibility was dramatically reduced in Ca(v)2.3-deficient mice, whereas 4-AP sensitivity remained unchanged.

Conclusions: Ca(v)2.3 ablation results in seizure resistance, strongly supporting recent findings in CA1 neurons that Ca(v)2.3 triggers epileptiform activity in specialized neurons via plateau potentials and afterdepolarizations. We provide novel insight into the functional involvement of Ca(v)2.3 in ictogenesis and seizure susceptibility on the whole-animal level.