Nonlinearities between GABAB Receptor-Mediated Inhibition and T-type Calcium Channel Activity Bidirectionally Regulate Thalamic Oscillations
Lu, Adam, Neuroscience - School of Medicine, University of Virginia
Beenhakker, Mark, MD-PHAR Pharmacology, University of Virginia
Absence seizures result from 3-5 Hz generalized thalamocortical oscillations that depend on highly regulated inhibitory neurotransmission in the thalamus. Efficient reuptake of the inhibitory neurotransmitter GABA is essential, and reuptake failure worsens seizures. Here, we show that blocking GABA transporters (GATs) in acute brain slices containing key parts of the thalamocortical seizure network modulates epileptiform activity. As expected, we found that blocking either GAT1 or GAT3 prolonged oscillations. However, blocking both GATs unexpectedly suppressed oscillations. Integrating experimental observations into single-neuron and network-level computational models shows how a non-linear dependence of T-type calcium channel opening on GABAB receptor activity regulates network oscillations. Receptor activity that is either too brief or too protracted fails to sufficiently open T-type channels necessary for sustaining oscillations. Only within a narrow range does prolonging GABAB receptor activity promote channel opening and intensify oscillations. These results have implications for therapeutics that modulate GABA transporters.
PHD (Doctor of Philosophy)
thalamic oscillations, thalamocortical neurons, network models, T-type calcium channels, GABAB receptors, inhibition kinetics, open probability discrepancy