Connexin 43 mimetic peptides inhibit spontaneous epileptiform activity in organotypic hippocampal slice cultures

• Published in: Experimental neurology Vol. 210; no. 2; pp. 762 - 775
• Main Authors: Samoilova, Marina, Wentlandt, Kirsten, Adamchik, Yana, Velumian, Alexander A., Carlen, Peter L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.04.2008; Elsevier
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Biological and medical sciences; Carbenoxolone; Carbenoxolone - pharmacology; Connexin 43; Connexins; Connexins - pharmacology; Electroencephalography - methods; Epilepsy - drug therapy; Epilepsy - physiopathology; Evoked Potentials - drug effects; Evoked Potentials - physiology; Evoked Potentials - radiation effects; Gap junctions; Glia; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus; Hippocampus - drug effects; Hippocampus - physiopathology; Medical sciences; Mimetic peptides; Nervous system (semeiology, syndromes); Neurology; Organ Culture Techniques; Organotypic cultures; Rats; Rats, Wistar; Seizures; Serum - metabolism; Time Factors; Carbenoxolone; Mimetic peptides; Organotypic cultures; Gap junctions; Connexins; Connexin 43; Glia; Hippocampus; Seizures; Nervous system diseases; Peptides; Epilepsy; Central nervous system; Cell junction; Gap junction; Encephalon; Cerebral disorder; Connexin; Convulsion; Central nervous system disease; Neurological disorder
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2008.01.005

Gap junctions are cytoplasmic channels connecting adjacent cells and mediating their electrical and metabolic coupling. Different cell types in the CNS express various gap junction forming proteins, the connexins, in a cell-specific manner. Using the general gap junctional blocker, carbenoxolone, and two synthetic connexin mimetic peptides, corresponding to amino acid sequences of segments within the second extracellular loop of connexin 43, we studied the role of gap junctions in the generation of epileptiform activity in rat organotypic hippocampal slice cultures. While carbenoxolone inhibited both spontaneous and evoked seizure-like events, connexin mimetic peptides selectively attenuated spontaneous recurrent epileptiform activity, and only after prolonged (> 10 h) treatment. The effects were mediated through reduced gap junctional coupling as indicated by suppressed fluorescent dye transfer between the cells. Assuming a selective inhibition of a connexin 43-dependent process by the mimetic peptides and preferential localization of this connexin isoform in astrocytes, the data suggest that, in developing hippocampal networks, the generation and/or initiation of spontaneous recurrent seizure-like activity may depend in large part upon the opening of glial gap junctions. Furthermore, this study shows that the use of a synthetic peptide that mimics a short sequence of a specific connexin isoform and, hence, blocks gap junctional communication in targeted cell types in the CNS, is a viable strategy for the modulation of cerebral activity.