Rebound burst firing in the reticular thalamus is not essential for pharmacological absence seizures in mice

Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11828-33. doi: 10.1073/pnas.1408609111. Epub 2014 Jul 28.

Abstract

Intrinsic burst and rhythmic burst discharges (RBDs) are elicited by activation of T-type Ca(2+) channels in the thalamic reticular nucleus (TRN). TRN bursts are believed to be critical for generation and maintenance of thalamocortical oscillations, leading to the spike-and-wave discharges (SWDs), which are the hallmarks of absence seizures. We observed that the RBDs were completely abolished, whereas tonic firing was significantly increased, in TRN neurons from mice in which the gene for the T-type Ca(2+) channel, CaV3.3, was deleted (CaV3.3(-/-)). Contrary to expectations, there was an increased susceptibility to drug-induced SWDs both in CaV3.3(-/-) mice and in mice in which the CaV3.3 gene was silenced predominantly in the TRN. CaV3.3(-/-) mice also showed enhanced inhibitory synaptic drive onto TC neurons. Finally, a double knockout of both CaV3.3 and CaV3.2, which showed complete elimination of burst firing and RBDs in TRN neurons, also displayed enhanced drug-induced SWDs and absence seizures. On the other hand, tonic firing in the TRN was increased in these mice, suggesting that increased tonic firing in the TRN may be sufficient for drug-induced SWD generation in the absence of burst firing. These results call into question the role of burst firing in TRN neurons in the genesis of SWDs, calling for a rethinking of the mechanism for absence seizure induction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / toxicity
  • Action Potentials
  • Animals
  • Calcium Channels, T-Type / deficiency
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / metabolism*
  • Disease Models, Animal
  • Electrophysiological Phenomena
  • Epilepsy, Absence / chemically induced
  • Epilepsy, Absence / physiopathology*
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Patch-Clamp Techniques
  • Thalamic Nuclei / physiopathology*

Substances

  • Cacna1h protein, mouse
  • Cacna1i protein, mouse
  • Calcium Channels, T-Type
  • 4-Butyrolactone