title: Thalamocortical neurons display suppressed burst-firing due to an enhanced Ih current in a genetic model of absence epilepsy.
abstract: Burst-firing in distinct subsets of thalamic relay (TR) neurons is thought to be a key requirement for the propagation of absence seizures. However, in the well-regarded Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model as yet there has been no link described between burst-firing in TR neurons and spike-and-wave discharges (SWDs). GAERS ventrobasal (VB) neurons are a specific subset of TR neurons that do not normally display burst-firing during absence seizures in the GAERS model, and here, we assessed the underlying relationship of VB burst-firing with Ih and T-type calcium currents between GAERS and non-epileptic control (NEC) animals. In response to 200-ms hyperpolarizing current injections, adult epileptic but not pre-epileptic GAERS VB neurons displayed suppressed burst-firing compared to NEC. In response to longer duration 1,000-ms hyperpolarizing current injections, both pre-epileptic and epileptic GAERS VB neurons required significantly more hyperpolarizing current injection to burst-fire than those of NEC animals. The current density of the Hyperpolarization and Cyclic Nucleotide-activated (HCN) current (Ih) was found to be increased in GAERS VB neurons, and the blockade of Ih relieved the suppressed burst-firing in both pre-epileptic P15-P20 and adult animals. In support, levels of HCN-1 and HCN-3 isoform channel proteins were increased in GAERS VB thalamic tissue. T-type calcium channel whole-cell currents were found to be decreased in P7-P9 GAERS VB neurons, and also noted was a decrease in CaV3.1 mRNA and protein levels in adults. Z944, a potent T-type calcium channel blocker with anti-epileptic properties, completely abolished hyperpolarization-induced VB burst-firing in both NEC and GAERS VB neurons.
authors: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 219-2185 East Mall, Vancouver, BC, Canada, V6T 1Z4.
authors: Stuart M
authors: SM
authors: Cain
authors: John R
authors: JR
authors: Tyson
authors: Karen L
authors: KL
authors: Jones
authors: Terrance P
authors: TP
authors: Snutch
mesh_terms: D000200:Action Potentials; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D004832:Epilepsy, Absence / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013788:Thalamus / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D012333:RNA, Messenger