Functional contribution of specific brain areas to absence seizures: role of thalamic gap‐junctional coupling

Abstract

The synchronized discharges typical of seizures have a multifactorial origin at molecular, cellular and network levels. During recent years, the functional role of gap-junctional coupling has received increased attention as a mechanism that may participate in seizure generation. We have investigated the possible functional roles of thalamic and hippocampal gap-junctional communication (GJC) in the generation of spike-and-wave discharges in a rodent model of atypical absence seizures. Seizures in this model spread throughout limbic, thalamic and neocortical areas. Rats were chronically implanted with cannulae to deliver drugs or saline, and local field potentials recordings were performed using intracerebral electrodes positioned in distinct brain areas. Initially, the effects on synaptic transmission of the gap-junctional blockers used in this study were determined. Neither carbenoxolone (CBX) nor 18-alpha-glycyrrhetinic acid altered chemical synaptic transmission at the concentrations tested. These two compounds, when injected via cannulae into the reticular nucleus of the thalamus (NRT), decreased significantly the duration of seizures as compared with saline injections or injections of the CBX inactive derivative glycyrrhizic acid. CBX injections into the hippocampus resulted in diminished seizure activity as well. NRT injections of trimethylamine, which presumably causes intracellular alkalinization (thereby promoting gap-junctional opening), enhanced seizures and spindle activity. These observations suggest that, in this rodent model, thalamic and limbic areas are involved in the synchronous paroxysmal activity and that GJC contributes to the spike-and-wave discharges.

Molecular Targets for Antiepileptic Drug Development

“…414 In vivo studies with gap junction blockers and openers have recently been performed in genetic and acquired rodent models of absence seizures. [415][416][417] These studies have established that systemically administered carbenoxolone can diminish spike-and-wave discharges and indicate that gap junctions play a role in the spread of seizure activity in the thalamus and the cortex. Moreover, the data identify connexins as plausible molecular targets for AED development.…”

Role of gap junctions in epilepsy

“…The broad-spectrum junction blocker carbenoxolone has anti-seizure properties in epilepsy models induced by amygdala kindling [105] , maximal electroshock [106] , 4-AP [71,72,107] , penicillin [108] and tetanus toxin [109] , as well as in the pentylenetetrazole model of seizures [106] , absence seizure models [102,110,111] and audiogenic seizure models [112,113] . The Cx43-selective junction blocker meclofenamic acid has anticonvulsant effects both in the maximal electroshock model [114] and in tetanus toxin-induced refractory focal cortical epilepsy [109] .…”

“…Pretreatment with the junction opener trimethylamine reverses the inhibitory effects of quinine on the latency and the duration of generalized tonic-clonic seizures induced by pentylenetetrazole [119] . In the amygdalakindled epilepsy model [105] , 4-AP-induced epilepsy [71,107,116] and a rodent model of atypical absence seizures [111] , the junction opener trimethylamine has a pro-convulsant effect.…”

“…A rodent model of atypical Long-Evans rat pups given Carbenoxolone and 18α-glycyrrhetinic acid injected into the reticular nucleus of the absence seizures subcutaneous cholesterol thalamus (NRT) decreases duration of seizures; carbenoxolone injections into the hippocampus synthesis inhibitor AY9944 result in diminished seizure activity; NRT injections of trimethylamine enhance seizures every 6 d from postnatal and spindle activity [111] . day (P)2 to P22 Table 6.…”

Termination of ongoing spike-wave discharges investigated by cortico–thalamic network analyses

“…Sohal et al (2003) as well as Proulx et al (2006) proposed that the reticular thalamic nucleus (RTN) might be involved in the control of SWD duration. They showed that selective pharmacological manipulations, which affect the intra RTN communication, significantly shortened SWD.…”