The Functional Significance of Gap Junction Channels in the Epileptogenicity and Seizure Susceptibility of Juvenile Rats

Abstract

Summary: Purpose:The functional significance of gapjunction (GJ) channels in seizure susceptibility and induction and maintenance of seizures in the developing rat brain was investigated on the 4-aminopyridine (4-AP) in vivo epilepsy model. Methods:In electrophysiological experiments, GJs were manipulated with a blocker or opener before induction or at the active epileptic foci between postnatal days 9 and 28 (P9-28). Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) amplification was used to measure the levels of connexin (Cx) 26, 32, 36, and 43 mRNAs at the untreated cortex or epileptic foci.Results: The basic electrocorticogram (ECoG) and Cx messenger RNA (mRNA) expression patterns exhibited characteristic maturation; the 4-AP-induced epileptiform activity correlated well with these changes. Cx mRNA expressions were significantly upregulated around P16 (except for Cx26). The Cx26, 36, and 43 gene inducibility was highest around P16 and then declined significantly. In the youngest animals, the GJ opener induced rhythmic synchronous cortical activity. On maturation, the seizures became focalized and periodic; the discharges accelerated their amplitude and frequency increase. A transient decrease (P13-14) and then increase (P15-16) in seizure susceptibility were followed by a tendency to periodicity and focalization.Conclusions: The study suggests that GJ communication is involved in rhythm genesis and synchronization of cortical activity and may enhance the epileptogenicity of the developing brain.Key Words: Gap junction channelsSynchrony-Connexins-Development-Epileptogenicity-4-Aminopyridine.Clinical experience and various experimental data indicate that the developing nervous system is more sensitive than the mature one to different convulsive effects (1-5). Although the physiological factors underlying this differential epileptogenicity have not been fully clarified, the higher susceptibility of the immature brain can be explained by certain characteristic neurobiologic features. The developing brain exhibits a high metabolic rate, abundant neuronal and synaptic networks, the overexpression of receptors and enzymes, the depolarizing effect of γ -amino-acid, the hypersynchrony of neuronal circuits, and enhanced synaptic plasticity (6,7). In addition, the immature cerebral cortex and hippocampus have higher densities of excitatory amino acid receptors and gap junction (GJ) channels as compared with the adult organs (4,8).Intercellular communication via GJ channels is an important form of cell-to-cell communication in early brain development (8)(9)(10)(11)(12)(13)(14). Electrical coupling via GJ channels has been reported both between pairs of inhibitory neurons and among inhibitory and excitatory neurons during the Accepted January 30, 2006. Address correspondence and reprint requests to Dr. M. Szente at Department of Comparative Physiology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary. E-mail: szente@bio.u-szeged.hu early postnatal days in the rat cortex (10). Moreover,...

Connexin36 knockout mice display increased sensitivity to pentylenetetrazol-induced seizure-like behaviors

“…Recently there has been increased interest in the role of gap junctional intercellular communication in modulating this synchronized activity (Gajda, et al 2006, Traub, et al 2004). …”

A Key Role for Connexin Hemichannels in Spreading Ischemic Brain Injury

“…Gajda and colleagues reported that, in anaesthetized adult rats, seizure amplitude and duration was reduced by the non-specific gap junction blocker carbenoxolone and potentiated by the gap junction opener trimethylamine after seizure induction with 4-aminopyridine [49]. They proposed that the increased epileptogenicity of the developing brain compared to adult brains is mediated by enhanced gap junction communication [48]. Interestingly when trimethylamine was applied 60 minutes after 4-aminopyri dine in postnatal rats, discrete seizures were replaced with periods of status epilepticus [48].…”

“…In epilepsy a number of connexins have been shown to be upregulated including Cx26, Cx36 and Cx43 in rats, and Cx43 in human post mortem brain tissue [39,48]. The role of gap junctions in the propagation of seizures has been extensively investigated.…”

Papel das sinapses elétricas em crises epilépticas

“…As descobertas deste estudo sugerem que as JC não estão apenas envolvidas na gênese rítmica e na sincronização da atividade cortical, mas também podem ser responsáveis pela elevada epileptogenicidade do cérebro em desenvolvimento. 13 Szente e cols. (2002) investigaram o papel das JC na indução e manifestação de crises induzidas por 4-AP no neocórtex de ratos.…”