Connexins in Neuronal and Glial Gap Junctions in CNS

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DESCRIPTION (provided by applicant): Gap junctions are paired membrane specializations composed of dense clusters of tubular transmembrane channels (connexons) that link head to head across the extracellular space, forming pathways for direct electrical coupling and intercellular exchange of ions and low molecular weight metabolites. In mammals, gap junctions are abundant between glial cells and recently have been discovered at "mixed" (electrical plus chemical) synapses between neurons. Gap junctions are composed of one or more of the 21 different connexin proteins identified in the two draft human genome sequences. At least 13 connexin proteins are expressed in mammalian CNS. Currently, there is considerable controversy as to which connexins are present in neurons vs. glia, and whether neurons are coupled to glia through conjoint gap junctions. Glial gap junctions provide pathways for maintaining ionic homeostasis throughout the CNS, whereas neuronal gap junctions, particularly those at mixed synapses, may underlie the production of high-frequency oscillations in neurons as the substrate for conscious perception and arousal from sleep, and they may be involved in the synchronous bursting activity of epilepsy. Because the specific pairing combinations of the several connexins expressed in each gap junction plaque provide for metabolic, voltage, and ionic regulation of gap junction conductance and gating properties, it is essential to determine the connexin composition of both neuronal and glial gap junctions in normal adult animals. It also is essential to determine if, in addition to linking neurons, gap junctions link neurons to glia. Thus, the long-term goals of the proposed research are to determine the relative abundance, histological and ultrastructural distribution, cellular coupling partners, and connexin compositions of gap junctions in neurons and glia in adult mammalian CNS.