Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic oscillations.

Adam C Lu,Christine Kyuyoung Lee,John R Huguenard,Mark P Beenhakker,Megan Wang,Max Kleiman-Weiner,Brian Truong

doi:10.7554/elife.59548

Abstract

Absence seizures result from 3 to 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 human seizures. Here, we show that blocking GABA transporters (GATs) in acute rat 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 gating 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 inhibition kinetics.

Highlights

Neural circuits rely on a combination of intrinsic cellular properties and synaptic connections to generate large-scale electrical oscillations that drive behavior (Getting, 1989; Marder and Calabrese, 1996; Nusbaum and Beenhakker, 2002; Huguenard and McCormick, 2007)
We investigate the consequences of physiologically-relevant GABAB receptor-mediated inhibition observed during different combinations of GABA transporter blockade: control, GAT1 blockade, GAT3 blockade and dual GAT1+GAT3 blockade (Beenhakker and Huguenard, 2010)
We explored whether the interplay between GABAB-mediated inhibition and T type calcium channel dynamics in thalamocortical neurons contributes to the observed changes in network-level oscillations following

Summary

Introduction

Neural circuits rely on a combination of intrinsic cellular properties and synaptic connections to generate large-scale electrical oscillations that drive behavior (Getting, 1989; Marder and Calabrese, 1996; Nusbaum and Beenhakker, 2002; Huguenard and McCormick, 2007) Following membrane hyperpolarization, such as that produced by synaptic inhibition, cortically-projecting neurons of the thalamus [i.e. thalamocortical (TC) neurons]. Several studies have shown that CaV3.1 T-type calcium channels (T channels) sustain post-inhibitory rebound bursts in thalamocortical neurons by producing a relatively prolonged calcium-dependent, low-threshold spike (Kim et al, 2001, 2003; Porcello et al, 2003) These channels require membrane depolarization to open and hyperpolarization to recover (Coulter et al, 1989). While controlled voltage-clamp experiments have informed our understanding of how neuronal membrane potential dynamics can affect T channel opening (Gutierrez et al, 2001), we still know little regarding channel behavior during physiological forms of synaptic inhibition

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