Breakdown of GABAergic Control in Thalamocortical Epilepsies

Absence epilepsy, characterized by brief seizures that spread throughout the brain, results from abnormal rhythmic activity between networks of thalamic and cortical neurons. Inhibitory GABAergic signaling among neurons of the reticular thalamic (RT) nucleus is proposed to form a critical choke point that normally prevents the generation of seizures. Neurons need to maintain low intracellular Cl- concentrations ([Cl-]i) to enable inhibitory neuronal responses to GABAA receptor-mediated signaling. The Cl- transporter KCC2 and extracellular impermeant anions ([A]o) of the extracellular matrix maintain a low [Cl-]i in RT neurons under basal conditions. However, low KCC2 expression reduces the Cl- extrusion capacity of RT neurons and facilitates [Cl-]i accumulation during periods of elevated GABAergic signaling. The thalamic choke point breaks down, allowing seizures to occur, when the [Cl-]i of RT neurons becomes sufficiently elevated to produce excitatory GABAergic signaling. The seizure-prone WAG/Rij strain of rats has reduced RT expression of both KCC2 and [A]o, potentially promoting the occurrence of spontaneous absence seizures. A more complete understanding of the mechanisms that enable inhibitory GABAergic signaling among RT neurons to form a critical seizure choke point has the potential to improve the treatments available to patients with absence epilepsy.