Electrical synaptic transmission requires a postsynaptic scaffolding protein

Lasseigne, Abagael M; Ijaz, Sundas; Michel, Jennifer Carlisle; Martin, Elizabeth A.; Marsh, Audrey J.; Trujillo, E.; Marsden, Kurt C.; Pereda, Alberto E.; Miller, Adam C.

doi:10.7554/elife.66898

Cited by 32 publications

(75 citation statements)

References 99 publications

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“…Connexins, yet it itself is necessary for these proteins to robustly localize to the developing synapse. Furthermore, we have identified a biochemical connection between Neurobeachin and ZO1b, and previous work found that ZO1b in turn binds Cx34.1 (Lasseigne et al, 2021). Thus, our emerging model is that Neurobeachin sits at the top of an electrical synapse hierarchy, directing ZO1b to the synapse, which in turn brings in the Connexin to build the neuronal gap junction.…”

Section: Discussionmentioning

confidence: 58%

“…Electrical synapse structure and function is built hierarchically wherein ZO1b is required for Connexin localization, but ZO1b largely localizes independently of the Connexins (Lasseigne et al, 2021). We therefore sought to determine if localization of Neurobeachin to the electrical synapse was dependent on ZO1b or Connexins.…”

Section: Resultsmentioning

confidence: 99%

“…In nbeaa-/- mutants, we observed similar decreases of both pre- and post-synaptic Connexin proteins at the synapses. Using a transgenic line that marks endogenous ZO1b with a V5 epitope (Lasseigne et al, 2021), we examined 5 dpf wildtype and nbeaa-/- mutant fish for ZO1b at CE (Figure 2C,G) and M/CoLo synapses (Figure 2F,H). We observe a similar loss of ZO1b at the electrical synapse in nbeaa-/- mutant fish.…”

Section: Resultsmentioning

confidence: 99%

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Neurobeachin controls the asymmetric subcellular distribution of electrical synapse proteins

Martin

Michel

Kissinger

et al. 2022

Preprint

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Brain function relies upon the carefully coordinated development of specialized synaptic connections between neurons. The subcellular positioning of synapses and their molecular composition regulate neural computation, forming the fundamental basis of neural circuits. Like chemical synapses, electrical synapses are constructed from an assortment of cell adhesion, scaffolding, and regulatory molecules, as well as channel-forming Connexin proteins, yet little is known about how these molecules localize at specified subcellular compartments of the neuron. Here we investigated the cell biological relationship between the autism- and epilepsy-associated gene Neurobeachin, the gap junction forming neuronal Connexins, and electrical synapse scaffold Zonula Occludens 1 (ZO1). Using the model electrical synapses of the zebrafish Mauthner circuit we found that Neurobeachin localizes to the electrical synapse independent of the ZO1 scaffold and Connexins. By contrast, we show that Neurobeachin functions postsynaptically where it is required for the robust localization of ZO1 and Connexins. We demonstrate that Neurobeachin binds ZO1 but not Connexin proteins. Finally, we find that Neurobeachin is required to restrict postsynaptic electrical synapse proteins to dendritic synapses. Altogether the findings reveal a mechanism for the asymmetric synaptic localization of electrical synapse components providing a basis for the subcellular specialization of neuronal gap junctions.

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Section: Discussionmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Neurobeachin controls the asymmetric subcellular distribution of electrical synapse proteins

Martin

Michel

Kissinger

et al. 2022

Preprint

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“…In our FIB-SEM material, and appropriately fixed SBF-SEM material, the pentalaminar structure of gap junctions cannot be resolved but an area of increased membrane density and chromophilic staining is present where the membranes of a cone telodendron and a rod spherule merge. The identity of the chromophilic material is unknown but presumably it represents the aggregation of connexons and auxiliary proteins at gap junction sites (Lasseigne et al, 2021;Nagy et al, 2018). For rod spherules, this coincides with the location of Cx36 labeling, close to the mouth of the synaptic opening, and so there is a high probability that these sites represent gap junctions.…”

Section: Identification Of Gap Junctionsmentioning

confidence: 94%

Analysis of Rod/Cone Gap Junctions from the Reconstruction of Mouse Photoreceptor Terminals

Massey¹,

Ishibashi²,

Keung³

et al. 2021

Preprint

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Using serial blockface-scanning electron microscopy (SBF-SEM) and focused ion beam-scanning electron microscopy (FIB-SEM), combined with confocal microscopy for the gap junction protein Cx36, we reconstructed mouse photoreceptor terminals and located the gap junctions between them. An exuberant spray of fine telodendria extends from each cone pedicle (including blue cones) to contact 40-50 nearby rod spherules where Cx36 clusters were located, close to the mouth of the synaptic opening. There were approximately Cx36 clusters per cone 50 pedicle and 2-3 per rod spherule. We were unable to detect rod/rod or cone/cone coupling. Thus, rod/cone coupling accounts for nearly all gap junctions between photoreceptors. Our calculations suggest a mean of 82 Cx36 channels between a rod/cone pair of which 25% are open at rest. Rod/cone gap junctions are modulated by dopamine. Comparing our morphological calculations of maximum coupling to previous physiological results suggests that dopamine antagonists can drive rod/cone gap junctions to a surprisingly high open probability, approaching 100%.

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“…Moreover, recent evidence suggests that proper function and plasticity of gap junctions depend on the interaction with multimolecular complexes composed of proteins involved in cell adhesion, scaffolding, trafficking, and protein kinases [ 8 , 9 , 10 ]. For instance, the scaffold protein zonula-occludens-1 has been shown to interact with the C-terminal tail of Cx34.1, homologous to mammalian Cx36 in fish, and its presence is essential for the structure and function of electrical synaptic transmission [ 11 , 12 ]. The cytoskeleton protein tubulin has also been shown to interact with Cx36 at the C-terminal domain, suggesting the existence of a tubulin-dependent transport involved in the regulation of gap junction resistance and size [ 13 ].…”

Section: Gap Junctions As the Structural Substrate Of Electrical Synapsesmentioning

confidence: 99%

Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms

Curti

Davoine

Dapino

2022

Biology

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Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals, they are mostly composed of the protein connexin36. Circuits of electrically coupled neurons are widespread in these animals. Plus, experimental and theoretical evidence supports the notion that, beyond synchronicity, these circuits are able to perform sophisticated operations such as lateral excitation and inhibition, noise reduction, as well as the ability to selectively respond upon coincident excitatory inputs. Although once considered stereotyped and unmodifiable, we now know that electrical synapses are subject to modulation and, by reconfiguring neural circuits, these modulations can alter relevant operations. The strength of electrical synapses depends on the gap junction resistance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage and ligand gated channels of the non-synaptic membrane critically determine the efficacy of transmission at these contacts. Consistently, modulatory actions on these channels have been shown to represent relevant mechanisms of plasticity of electrical synaptic transmission. Here, we review recent evidence on the regulation of electrical synapses of mammals, the underlying molecular mechanisms, and the possible ways in which they affect circuit function.

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Electrical synaptic transmission requires a postsynaptic scaffolding protein

Cited by 32 publications

References 99 publications

Neurobeachin controls the asymmetric subcellular distribution of electrical synapse proteins

Neurobeachin controls the asymmetric subcellular distribution of electrical synapse proteins

Analysis of Rod/Cone Gap Junctions from the Reconstruction of Mouse Photoreceptor Terminals

Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms

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