The ever-changing electrical synapse

O’Brien, John

doi:10.1016/j.conb.2014.05.011

Cited by 73 publications

(63 citation statements)

References 42 publications

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“…Just as for the increased amplitude we observed in juvenile Cx36 −/− mice in DD, reduced amplitude in juvenile Cx36 −/− mice in LD conditions (our study) or in adult Cx36 −/− mice (Long, et al, 2005) may be related to deficiencies outside the SCN, e.g. in the light input pathway in the retina (O'Brien, 2014), and not necessarily due to altered coupling among SCN cells.…”

Section: Discussionsupporting

confidence: 66%

Cellular circadian oscillators in the suprachiasmatic nucleus remain coupled in the absence of connexin-36

et al. 2017

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In mammals, the master circadian clock resides in the suprachiasmatic nucleus (SCN). The SCN is characterized by robust circadian oscillations of clock gene expression and neuronal firing. The synchronization of circadian oscillations among individual cells in the SCN is attributed to intercellular coupling. Previous studies have shown that gap junctions, specifically those composed of connexin-36 (Cx36) subunits, are required for coupling of electrical firing among SCN neurons at a time scale of milliseconds. However, it remains unknown whether Cx36 gap junctions also contribute to coupling of circadian (~24 h) rhythms of clock gene expression. Here, we investigated circadian expression patterns of the clock gene Period 2 (Per2) in the SCN of Cx36-deficient mice using luminometry and single-cell bioluminescence imaging. Surprisingly, we found that synchronization of circadian PER2 expression rhythms is maintained in SCN explants from Cx36-deficient mice. Since Cx36 expression levels change with age, we also tested circadian running-wheel behavior of juvenile (3–4 weeks old) and adult (9–30 weeks old) Cx36-deficient mice. We found that impact of connexin-36 expression on circadian behavior changes greatly during postnatal development. However, consistent with the intact synchrony among SCN cells in cultured explants, Cx36-deficient mice had intact locomotor circadian rhythms, although adults displayed a lengthened period in constant darkness. Our data indicate that even though Cx36 may be required for electrical coupling of SCN cells, it does not affect coupling of molecular clock gene rhythms. Thus, electrical coupling of neurons and coupling of circadian clock gene oscillations can be regulated independently in the SCN.

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Section: Discussionsupporting

confidence: 66%

Cellular circadian oscillators in the suprachiasmatic nucleus remain coupled in the absence of connexin-36

et al. 2017

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“…Our findings raise an alternative possibility, that ESD asymmetry might differentially regulate pre- and postsynaptic Cxs providing a platform for functional asymmetry. Scaffold asymmetry may allow differential phosphorylation of Cx hemichannels[27] or may alter the local intracellular milieu in a manner that differentially gates the Cxs[28]. It is intriguing to note that in cases where Cxs are symmetric, the nervous system might use ESD asymmetry to create differential pre- and postsynaptic functions at electrical synapses.…”

Section: Discussionmentioning

confidence: 99%

Asymmetry of an Intracellular Scaffold at Vertebrate Electrical Synapses

et al. 2017

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Summary Neuronal synaptic connections are either chemical or electrical, and these two types of synapses work together to dynamically define neural circuit function[1]. While we know a great deal about the molecules that support chemical synapse formation and function, we know little about the macromolecular complexes that regulate electrical synapses. Electrical synapses are created by gap junction channels (GJs) that provide direct ionic communication between neurons[2]. While often molecularly and functionally symmetric, recent work has found that pre- and postsynaptic neurons can contribute different GJ-forming proteins, creating molecularly asymmetric channels that are correlated with functional asymmetry at the synapse[3,4]. Associated with the GJs are structures observed by electron microscopy termed the Electrical Synapse Density (ESD)[5]. The ESD has been suggested to be critical for the formation and function of the electrical synapse, yet the biochemical makeup of these structures is poorly understood. Here we find that electrical synapse formation in vivo requires an intracellular scaffold called Tight Junction Protein 1b (Tjp1b). Tjp1b is localized to the electrical synapse where it is required for the stabilization of the GJs and for electrical synapse function. Strikingly, we find that Tjp1b protein localizes and functions asymmetrically, exclusively on the postsynaptic side of the synapse. Our findings support a novel model of electrical synapse molecular asymmetry at the level of an intracellular scaffold that is required for building the electrical synapse. We propose that such ESD asymmetries could be used by all nervous systems to support molecular and functional asymmetries at electrical synapses.

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“…Electrical synapses display a great deal of functional plasticity, being subject to alterations in coupling strength due to biophysical properties of the coupled cells, activity-dependent modification of the synapses, and modification driven by neurotransmitters (Pereda et al, 2013;O'Brien, 2014). The mechanisms responsible for these forms of plasticity are of great interest.…”

Section: Contribution Of Cx36 Turnover To Electrical Synaptic Plasticitymentioning

confidence: 99%

Two-color fluorescent analysis of connexin 36 turnover: relationship to functional plasticity

Wang

Lin

Mitchell

et al. 2015

Journal of Cell Science

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Gap junctions formed of connexin 36 (Cx36, also known as Gjd2) show tremendous functional plasticity on several time scales. Changes in connexin phosphorylation modify coupling in minutes through an order of magnitude, but recent studies also imply involvement of connexin turnover in regulating cell-cell communication. We utilized Cx36 with an internal HaloTag to study Cx36 turnover and trafficking in cultured cells. Irreversible, covalent pulse-chase labeling with fluorescent HaloTag ligands allowed clear discrimination of newly formed and pre-existing Cx36. Cx36 in junctional plaques turned over with a half-life of 3.1 h, and the turnover rate was unchanged by manipulations of protein kinase A (PKA) activity. In contrast, changes in PKA activity altered coupling within 20 min. New Cx36 in cargo vesicles was added directly to existing gap junctions and newly made Cx36 was not confined to points of addition, but diffused throughout existing gap junctions. Existing connexins also diffused into photobleached areas with a half-time of less than 2 s. In conclusion, studies of Cx36-HaloTag revealed novel features of connexin trafficking and demonstrated that phosphorylation-based changes in coupling occur on a different time scale than turnover.

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The ever-changing electrical synapse

Cited by 73 publications

References 42 publications

Cellular circadian oscillators in the suprachiasmatic nucleus remain coupled in the absence of connexin-36

Cellular circadian oscillators in the suprachiasmatic nucleus remain coupled in the absence of connexin-36

Asymmetry of an Intracellular Scaffold at Vertebrate Electrical Synapses

Two-color fluorescent analysis of connexin 36 turnover: relationship to functional plasticity

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