Thalamic Modulation of Cingulate Seizure Activity Via the Regulation of Gap Junctions in Mice Thalamocingulate Slice

Wei-Pang Chang,Bai-Chuang Shyu,José Jiun-Shian Wu,Andrej A Romanovsky

doi:10.1371/journal.pone.0062952

Abstract

The thalamus is an important target for deep brain stimulation in the treatment of seizures. However, whether the modulatory effect of thalamic inputs on cortical seizures occurs through the modulation of gap junctions has not been previously studied. Therefore, we tested the effects of different gap junction blockers and couplers in a drug-resistant seizure model and studied the role of gap junctions in the thalamic modulation on cortical seizures. Multielectrode array and calcium imaging were used to record the cortical seizures induced by 4-aminopyridine (250 µM) and bicuculline (5–50 µM) in a novel thalamocingulate slice preparation. Seizure-like activity was significantly attenuated by the pan-gap junction blockers carbenoxolone and octanol and specific neuronal gap junction blocker mefloquine. The gap junction coupler trimethylamine significantly enhanced seizure-like activity. Gap junction blockers did not influence the initial phase of seizure-like activity, but they significantly decreased the amplitude and duration of the maintenance phase. The development of seizures is regulated by extracellular potassium concentration. Carbenoxolone partially restored the amplitude and duration after removing the thalamic inputs. A two-dimensional current source density analysis showed that the sink and source signals shifted to deeper layers after removing the thalamic inputs during the clonic phase. These results indicate that the regulatory mechanism of deep brain stimulation in the thalamus occurs partially though gap junctions.

Highlights

Seizures affect 1% of the population worldwide, and 30% of affected patients have drug-resistant epilepsy [1]
Seizure-like activity induced by 4-AP and bicuculline were divided into ictal onset (Fig. 1B, arrow), a tonic phase (Fig. 1B, green line), and a clonic phase (Fig. 1B, red line) based on frequency evolution shown by wavelet transformed from field potential recording [41]
Paired extra- and intracellular recordings showed that the tonic phase corresponded to the depolarization of pyramidal neurons, and the clonic phase corresponded to the bursting activity of pyramidal neurons (Fig. 1C)

Summary

Introduction

Seizures affect 1% of the population worldwide, and 30% of affected patients have drug-resistant epilepsy [1]. Evidence shows that gap junctions are involved in pathophysiological hyper-synchrony during seizure activity [3,4,5,6]. Growing studies seek to regulate gap junctions to modulate seizures. Gap junctions exist between interneurons in the neocortex [7] and are important in regulating synchrony between interneurons. Gap junctions are expressed on glial cells [8]. The role of glial cells in seizures is to regulate the ionic concentration of the extracellular space and prevent the accumulation of potassium-generating neurons that become more excitable [9], [10]

Methods

Results

Conclusion