Involvement of Gap Junctions in the Manifestation and Control of the Duration of Seizures in Rats In Vivo

  • Gajda Z
  • Gyengési E
  • Hermesz E
 et al. 
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Abstract

PURPOSE: The possible role of gap junctions in the manifestation and control of the duration of seizures was tested on the 4-aminopyridine–induced epilepsy model in rats in vivo, by using electrophysiologic, pharmaco-logic, and molecular biologic techniques. METHODS: In electrophysiologic experiments, the func-tional states of the gap junctions were manipulated with a specific blocker (carbenoxolone) or opener (trimethy-lamine) at the already active focus of adult, anesthetized rats, 60 min after the induction of the first seizure, which was repeated spontaneously thereafter. Semi-quantitative reverse transcriptase-polymerase chain re-action (RT-PCR) amplification was used to measure the levels of connexin (Cx) 32, 43, and 36 messenger RNAs (mRNAs) prepared from the areas of the already active primary and mirror foci. RESULTS: After repeated seizures, the expression lev-els of Cx32, Cx43, and Cx36 mRNAs at the epileptic foci were increased significantly. Blockade of the gap junctions with carbenoxolone shortened the duration of seizures and decreased the amplitude of the seizure discharges, whereas their opening with trimethylamine lengthened the duration and increased the amplitude. Secondary epileptogenesis was facilitated when the gap junctions were opened. CONCLUSIONS: Our findings support the idea that, in epileptic foci, the gap junctions are involved in the ex-pression of rhythmic ictal discharges and in the control of the duration and propagation of the individual seizures in vivo. COMMENTARY G ap junctions in the mammalian brain allow rapid inter-cellular communication via a nonsynaptic mechanism. Through gap junctions, electrical activity can spread rapidly, synchronizing a local neuronal network. Such rapid coupling has obvious implications for the synchronization and spread of seizure activity (1,2). The involvement of gap junctions in epilepsy is appealing but controversial. Although fast, nonsy-naptic electrical transmission can potentially facilitate the gen-eration and spread of seizure activity in the brain, it has long been debated whether gap junctions are sufficiently plentiful and strategically placed to enhance neuronal synchrony to the extent that epileptic firing is augmented (3). Two lines of investigation may shed light on this contro-versy. First, rapidly increasing knowledge exists about the molec-ular biology of gap junctions. Gap junctions are composed of connexins—intramembranous protein complexes from adjoin-ing cell membranes (neurons or glia), the pore of which allows intercellular passage of current (usually as K + ions) and other small molecules. At least 10 different connexins are expressed in the mammalian central nervous system, and this diversity en-dows gap junctions with a panoply of physiological properties, depending on the type and stoichiometry of the particular con-nexins (4,5). Other new techniques, such as cloning of connexin genes, in situ hybridization, and production of transgenic mice have allowed investigators to begin unraveling the complexities and functions of gap junctions in the brain. Gap junctions can now be visualized in vivo and in vitro, complementing the elec-tron microscopy studies that initially verified their existence. The second research trend is the discovery that gap junc-tional transmission is rapidly modifiable. Electrical synapses do not have fixed properties; rather, rapid changes in coupling strength have now been shown in response to a variety of neu-rotransmitters, phosphorylation, second messengers, and other modulators, such as nitric oxide. In particular, the availability of agents that rapidly open or close gap junctions has permitted investigators to probe the functional role of gap junctions in a variety of physiological conditions, including epilepsy (6). In this article and in previous work (7), Gajda et al. ex-ploited these recent experimental advances to study the role of gap junctions during a seizure in intact animals. They in-duced repetitive seizures in anesthetized adult rats, by using local application of 4-aminopyridine (4-AP) on somatosensory neocortex. Electrographic seizure activity was recorded from the injection site (primary focus) and from homotopic cor-tex in the opposite hemisphere (mirror focus). Electrographic seizure frequency, duration, and amplitude were documented

Author-supplied keywords

  • 4-AP-induced seizure
  • Carbenoxolone
  • Connexins
  • Gap junctions
  • Trimethylamine

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Authors

  • Zita Gajda

  • Erika Gyengési

  • Edit Hermesz

  • K. Said Ali

  • Magdolna Szente

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