Ca(V)3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons
AuthorCain, SM; Tyson, JR; Choi, H-B; Ko, R; Lin, PJC; LeDue, JM; Powell, KL; Bernier, L-P; Rungta, RL; Yang, Y; ...
Document TypeJournal Article
CitationsCain, S. M., Tyson, J. R., Choi, H. -B., Ko, R., Lin, P. J. C., LeDue, J. M., Powell, K. L., Bernier, L. -P., Rungta, R. L., Yang, Y., Cullis, P. R., O'Brien, T. J., MacVicar, B. A. & Snutch, T. P. (2018). Ca(V)3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons. EPILEPSIA, 59 (4), pp.778-791. https://doi.org/10.1111/epi.14018.
Access StatusOpen Access
OBJECTIVE: Genetic alterations have been identified in the CACNA1H gene, encoding the CaV 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 CaV 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 CaV 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 CaV 3.2 mutation-sensitive splice variant. In vivo knock-down of CaV 3.2 using direct thalamic injection of lipid nanoparticles containing CaV 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 CaV 3.2 T-type channels in propagating thalamocortical network seizures and setting the pacemaking frequency of SWDs.
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