Reduction of high‐frequency network oscillations (ripples) and pathological network discharges in hippocampal slices from connexin 36‐deficient mice

Maier, Nikolaus; Güldenagel, Martin; Söhl, Goran; Siegmund, Herbert; Willecke, Klaus; Draguhn, Andreas

doi:10.1113/jphysiol.2002.017624

Cited by 173 publications

(132 citation statements)

References 39 publications

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“…Interestingly, very fast oscillations were unaffected in mice lacking Cx36 (32,33), suggesting that gap junction proteins in addition to Cx36 may contribute to the formation of axoaxonic gap junctions. On the other hand, another study has reported a decreased incidence of in vitro high-frequency ripples in a Cx36 knockout mouse (34).…”

Section: Discussionmentioning

confidence: 99%

Gap junctions on hippocampal mossy fiber axons demonstrated by thin-section electron microscopy and freeze–fracture replica immunogold labeling

Hamzei-Sichani¹,

Kamasawa

Janssen³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

140

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Gap junctions have been postulated to exist between the axons of excitatory cortical neurons based on electrophysiological, modeling, and dye-coupling data. Here, we provide ultrastructural evidence for axoaxonic gap junctions in dentate granule cells. Using combined confocal laser scanning microscopy, thin-section transmission electron microscopy, and grid-mapped freeze-fracture replica immunogold labeling, 10 close appositions revealing axoaxonic gap junctions (Ϸ30 -70 nm in diameter) were found between pairs of mossy fiber axons (Ϸ100 -200 nm in diameter) in the stratum lucidum of the CA3b field of the rat ventral hippocampus, and one axonal gap junction (Ϸ100 connexons) was found on a mossy fiber axon in the CA3c field of the rat dorsal hippocampus. Immunogold labeling with two sizes of gold beads revealed that connexin36 was present in that axonal gap junction. These ultrastructural data support computer modeling and in vitro electrophysiological data suggesting that axoaxonic gap junctions play an important role in the generation of very fast (>70 Hz) network oscillations and in the hypersynchronous electrical activity of epilepsy.axoaxonic ͉ connexin ͉ electrical synapse ͉ epilepsy ͉ synchronization

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Section: Discussionmentioning

confidence: 99%

Gap junctions on hippocampal mossy fiber axons demonstrated by thin-section electron microscopy and freeze–fracture replica immunogold labeling

Hamzei-Sichani¹,

Kamasawa

Janssen³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

140

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“…404 In oligodendrocytes, Cx32 and Cx47 provide nutrients to the myelin sheaths. 405 Connexin knockout studies in mice present a very mixed picture of developmental defects and some changes in oscillatory potentials in slice preparations, 406,407 but are difficult to interpret because of possible compensatory changes in other connexins. Recent studies indicate that knockout of the major neuronal gap junction protein Cx36 promotes epileptic hyperexcitability, suggesting that specific inhibitors would not be useful as AEDs.…”

Section: Gap Junctions (Connexins)mentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…Disruption of the Cx36 gene in mice results in deficits in visual transmission through the rod pathway (Guldenagel et al, 2001;Deans et al, 2002), consistent with disruption of AII amacrine-cone ON bipolar cell and rod-cone gap junctions. Cx36-null mice also showed impaired firing synchrony (Deans et al, 2001) and gamma-frequency oscillations (Hormuzdi et al, 2001) in the neocortex, and anomalous patterns of sharp-wave bursts and ripple oscillations in the hippocampus (Maier et al, 2002;Pais et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Connexin 35/36 is phosphorylated at regulatory sites in the retina

Kothmann

Li²,

Burr

et al. 2007

Vis Neurosci

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Connexin 35/36 is the most widespread neuronal gap junction protein in the retina and central nervous system. Electrical and/or tracer coupling in a number of neuronal circuits that express this connexin are regulated by light adaptation. In many cases the regulation of coupling depends on signaling pathways that activate protein kinases such as PKA, and Cx35 has been shown to be regulated by PKA phosphorylation in cell culture systems. To examine whether phosphorylation might regulate Cx35/36 in the retina we developed phospho-specific polyclonal antibodies against the two regulatory phosphorylation sites of Cx35 and examined the phosphorylation state of this connexin in the retina. Western blot analysis with hybrid bass retinal membrane preparations showed Cx35 to be phosphorylated at both the Ser110 and Ser276 sites, and this labeling was eliminated by alkaline phosphatase digestion. The homologous sites of mouse and rabbit Cx36 were also phosphorylated in retinal membrane preparations. Quantitative confocal immunofluorescence analysis showed gap junctions identified with a monoclonal anti-Cx35 antibody to have variable levels of phosphorylation at both the Ser110 and Ser276 sites. Unusual gap junctions that could be identified by their large size (up to 32 μm 2 ) and location in the IPL showed a prominent shift in phosphorylation state from heavily phosphorylated in nighttime, dark-adapted retina to weakly phosphorylated in daytime, light-adapted retina. Both Ser110 and Ser276 sites showed significant changes in this manner. Under both lighting conditions other gap junctions varied from non-phosphorylated to heavily phosphorylated. We predict that changes in the phosphorylation states of these sites correlate with changes in the degree of coupling through Cx35/36 gap junctions. This leads to the conclusion that connexin phosphorylation mediates changes in coupling in some retinal networks. However, these changes are not global and likely occur in a cell type-specific or possibly a gap junction-specific manner.

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Reduction of high‐frequency network oscillations (ripples) and pathological network discharges in hippocampal slices from connexin 36‐deficient mice

Cited by 173 publications

References 39 publications

Gap junctions on hippocampal mossy fiber axons demonstrated by thin-section electron microscopy and freeze–fracture replica immunogold labeling

Gap junctions on hippocampal mossy fiber axons demonstrated by thin-section electron microscopy and freeze–fracture replica immunogold labeling

Molecular Targets for Antiepileptic Drug Development

Connexin 35/36 is phosphorylated at regulatory sites in the retina

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