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.
Highlights
Burst-firing of neurons in the thalamocortical system is a characteristic feature accompanying the spike-and-wave discharges (SWDs) observed on electroencephalography (EEG) recordings during absence seizures, as well as being associated with other types of generalized and partial-onset epilepsies [4, 14]
We examined pre-epileptic P15–P20 non-epileptic control (NEC) versus Genetic Absence Epilepsy Rats from Strasbourg (GAERS) VB neurons in order to establish whether the observed attenuated ability to induce burst-firing occurred in conjunction with seizure development
Distinct from that of adult animals, in P15–P20 animals, no significant difference was observed between GAERS and NEC for the amount of current injection required to induce rebound burst-firing in VB neurons with a 200-ms current step (NEC=−45.3±4.1 pA, GAERS=−43.6±7.2 pA; p=0.8; Fig. 1a left panels, b)
Summary
Burst-firing of neurons in the thalamocortical system is a characteristic feature accompanying the spike-and-wave discharges (SWDs) observed on electroencephalography (EEG) recordings during absence seizures, as well as being associated with other types of generalized and partial-onset epilepsies [4, 14]. Simultaneous EEG and intracellular recordings have defined TR regions that burst-fire in a phase-locked manner with SWDs in some animal models of absence seizures [19, 21, 41], which suggests that these regions are critical in the generation and/or propagation of seizure activity. Enhanced low-threshold T-type calcium currents can contribute towards the hyperexcitable burst-firing of TR neurons and are thought to induce or aid the propagation of absence seizures [7, 18]. Knockdown of the CaV3.1 T-type calcium channel expressed in TR neurons has been shown to protect against pharmacologically induced absence seizures [26, 43]
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