Ca 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons.

OBJECTIVE

Genetic alterations have been identified in the CACNA1H gene, encoding the Ca 3.2 T-type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation and spike-wave-discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of Ca 3.2 calcium channels, and we investigated whether a gain-of-function mutation in the Cacna1h gene in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) contributes to seizure propagation and pacemaking in the TRN.

METHODS

Pathophysiological contributions of Ca 3.2 calcium channels to burst firing and absence seizures were assessed in vitro using acute brain slice electrophysiology and quantitative real-time polymerase chain reaction (PCR) and in vivo using free-moving electrocorticography recordings.

RESULTS

TRN neurons from GAERS display sustained oscillatory burst-firing that is both age- and frequency-dependent, occurring only in the frequencies overlapping with GAERS SWDs and correlating with the expression of a Ca 3.2 mutation-sensitive splice variant. In vivo knock-down of Ca 3.2 using direct thalamic injection of lipid nanoparticles containing Ca 3.2 dicer small interfering (Dsi) RNA normalized TRN burst-firing, and in free-moving GAERS significantly shortened seizures.

SIGNIFICANCE

This supports a role for TRN Ca 3.2 T-type channels in propagating thalamocortical network seizures and setting the pacemaking frequency of SWDs.