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Electrical synapses with diverse configurations and functions occur at a variety of interneuronal appositions, thereby significantly expanding the physiological complexity of neuronal circuitry over that provided solely by chemical synapses. Gap junctions between apposed dendritic and somatic plasma membranes form "purely electrical" synapses that allow for electrical communication between coupled neurons. In addition, gap junctions at axon terminals synapsing on dendrites and somata allow for "mixed" (dual chemical+electrical) synaptic transmission. "Dual transmission" was first documented in the autonomic nervous system of birds, followed by its detection in the central nervous systems of fish, amphibia, and reptiles. Subsequently, mixed synapses have been detected in several locations in the mammalian CNS, where their properties and functional roles remain undetermined. Here, we review available evidence for the presence, complex structural composition, and emerging functional properties of mixed synapses in the mammalian CNS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In the neocortex, inhibitory interneurons of the same subtype are electrically coupled with each other via dendritic gap junctions (GJs). The impact of multiple GJs on the biophysical properties of interneurons and thus on their input processing is unclear. The present experimentally based theoretical study examined GJs in L2/3 large basket cells (L2/3 LBCs) with 3 goals in mind: (1) To evaluate the errors due to GJs in estimating the cable properties of individual L2/3 LBCs and suggest ways to correct these errors when modeling these cells and the networks they form; (2) to bracket the GJ conductance value (0.05-0.25 nS) and membrane resistivity (10 000-40 000 Ω cm(2)) of L2/3 LBCs; these estimates are tightly constrained by in vitro input resistance (131 ± 18.5 MΩ) and the coupling coefficient (1-3.5%) of these cells; and (3) to explore the functional implications of GJs, and show that GJs: (i) dynamically modulate the effective time window for synaptic integration; (ii) improve the axon's capability to encode rapid changes in synaptic inputs; and (iii) reduce the orientation selectivity, linearity index, and phase difference of L2/3 LBCs. Our study provides new insights into the role of GJs and calls for caution when using in vitro measurements for modeling electrically coupled neuronal networks., (© The Author 2016. Published by Oxford University Press.)

Precise spike synchrony has been widely reported in the central nervous system, but its functional role in encoding, processing, and transmitting information is yet unresolved. Of particular interest is firing synchrony between inhibitory cortical interneurons, thought to drive various cortical rhythms such as gamma oscillations, the hallmark of cognitive states. Precise synchrony can arise between two interneurons connected electrically, through gap junctions, chemically, through fast inhibitory synapses, or dually, through both types of connections, but the properties of synchrony generated by these different modes of connectivity have never been compared in the same data set. In the present study we recorded in vitro from 152 homotypic pairs of two major subtypes of mouse neocortical interneurons: parvalbumin-containing, fast-spiking (FS) interneurons and somatostatin-containing (SOM) interneurons. We tested firing synchrony when the two neurons were driven to fire by long, depolarizing current steps and used a novel synchrony index to quantify the strength of synchrony, its temporal precision, and its dependence on firing rate. We found that SOM-SOM synchrony, driven solely by electrical coupling, was less precise than FS-FS synchrony, driven by inhibitory or dual coupling. Unlike SOM-SOM synchrony, FS-FS synchrony was strongly firing rate dependent and was not evident at the prototypical 40-Hz gamma frequency. Computer simulations reproduced these differences in synchrony without assuming any differences in intrinsic properties, suggesting that the mode of coupling is more important than the interneuron subtype. Our results provide novel insights into the mechanisms and properties of interneuron synchrony and point out important caveats in current models of cortical oscillations., (Copyright © 2015 the American Physiological Society.)

• Connexin36 is highly expressed in sympathetic preganglionic neurons (SPNs). • Connnexin36 is detected along the entire length of the spinal thoracic intermediolateral cell column. • The IML contains glutamatergic and GABAergic terminals that are eGFP+ in Cx36BAC::eGFP mice. • SPNs are innervated by eGFP+ terminals in Cx36BAC::eGFP mice. Spinal sympathetic preganglionic neurons (SPNs) are among the many neuronal populations in the mammalian central nervous system (CNS) where there is evidence for electrical coupling between cell pairs linked by gap junctions composed of connexin36 (Cx36). Understanding the organization of this coupling in relation to autonomic functions of spinal sympathetic systems requires knowledge of how these junctions are deployed among SPNs. Here, we document the distribution of immunofluorescence detection of Cx36 among SPNs identified by immunolabelling of their various markers, including choline acetyltransferase, nitric oxide and peripherin in adult and developing mouse and rat. In adult animals, labelling of Cx36 was exclusively punctate and dense concentrations of Cx36-puncta were distributed along the entire length of the spinal thoracic intermediolateral cell column (IML). These puncta were also seen in association with SPN dendritic processes in the lateral funiculus, the intercalated and central autonomic areas and those within and extending medially from the IML. All labelling for Cx36 was absent in spinal cords of Cx36 knockout mice. High densities of Cx36-puncta were already evident among clusters of SPNs in the IML of mouse and rat at postnatal days 10–12. In Cx36BAC::eGFP mice, eGFP reporter was absent in SPNs, thus representing false negative detection, but was localized to some glutamatergic and GABAergic synaptic terminals. Some eGFP+ terminals were found contacting SPN dendrites. These results indicate widespread Cx36 expression in SPNs, further supporting evidence of electrical coupling between these cells, and suggest that SPNs are innervated by neurons that themselves may be electrically coupled. [ABSTRACT FROM AUTHOR]

• Gap junction-mediated inter-neuronal communication is regulated by mGluRs. • mGluRs trigger long-term changes in electrical synaptic transmission. • mGluR actions on electrical synapses might also involve other neurotransmitters. • These interactions play relevant roles during neurodevelopment and brain injury. Variations of synaptic strength are thought to underlie forms of learning and can functionally reshape neural circuits. Metabotropic glutamate receptors play key roles in regulating the strength of chemical synapses. However, information within neural circuits is also conveyed via a second modality of transmission: gap junction-mediated synapses. We review here evidence indicating that metabotropic glutamate receptors also play important roles in the regulation of synaptic communication mediated by neuronal gap junctions, also known as 'electrical synapses'. Activity-driven interactions between metabotropic glutamate receptors and neuronal gap junctions can lead to long-term changes in the strength of electrical synapses. Further, the regulatory action of metabotropic glutamate receptors on neuronal gap junctions is not restricted to adulthood but is also of critical relevance during brain development and contributes to the pathological mechanisms that follow brain injury. [ABSTRACT FROM AUTHOR]

Electrical coupling between neurons is broadly present across brain areas and is typically assumed to synchronize network activity. However, intrinsic properties of the coupled cells can complicate this simple picture. Many cell types with electrical coupling show a diversity of post-spike subthreshold fluctuations, often linked to subthreshold resonance, which are transmitted through electrical synapses in addition to action potentials. Using the theory of weakly coupled oscillators, we explore the effect of both subthreshold and spike-mediated coupling on synchrony in small networks of electrically coupled resonate-and-fire neurons, a hybrid neuron model with damped subthreshold oscillations and a range of post-spike voltage dynamics. We calculate the phase response curve using an extension of the adjoint method that accounts for the discontinuous post-spike reset rule. We find that both spikes and subthreshold fluctuations can jointly promote synchronization. The subthreshold contribution is strongest when the voltage exhibits a significant post-spike elevation in voltage, or plateau potential. Additionally, we show that the geometry of trajectories approaching the spiking threshold causes a "reset-induced shear" effect that can oppose synchrony in the presence of network asymmetry, despite having no effect on the phase-locking of symmetrically coupled pairs. [ABSTRACT FROM AUTHOR]

During the last decades it became increasingly evident that electrical synapses are capable of activity-dependent plasticity. However, measuring the actual strength of electrical transmission remains difficult. Usually changes in coupling strength can only be inferred indirectly from measures such as the coupling coefficient and the coupling conductance. Because these are affected by both junctional and non-junctional conductance, plastic changes can potentially be due to both components. Furthermore, these techniques also require the blocking of chemical transmission, so that processes that involve crosstalk between chemical and electrical synapses will be suppressed. To directly examine the magnitude of errors that can occur, we use dual whole-cell current- and voltage-clamp recordings from the soma of the pair of easily accessible, electrically coupled Retzius cells in the leech to simultaneously determine coupling coefficients, coupling conductances and directly measured gap junctional currents. We present the first direct and comparative analysis of gap junction conductance using all three methods and analyze how each method would characterize the response of gap junctions to serotonin. The traditional coupling coefficients showed severe deficits in assessing the symmetry and strength of electrical synapses. These were reduced when coupling conductances were determined and were absent in the direct method. Additionally, both coupling coefficient and coupling conductance caused large and systematic errors in assessing the size and time course of the serotonin-induced changes of gap junctional currents. Most importantly, both measurements can easily be misinterpreted as implying long-term gap junctional plasticity, although the direct measurements confirm its absence. We thus show directly that coupling coefficients and coupling conductances can severely confound plastic changes in membrane and junctional conductance. Wherever possible, voltage clamp measurements should be chosen to accurately characterize the timing and strength of plasticity of electrical synapses. However, we also demonstrate that coupling coefficients can still yield a qualitatively correct picture when amended by independent measurements of the course of membrane resistance during the experiments. [ABSTRACT FROM AUTHOR]

Intimate structural and functional relationships between gap junctions and adherens junctions have been demonstrated in peripheral tissues, but have not been thoroughly examined in the central nervous system, where adherens junctions are often found in close proximity to neuronal gap junctions. Here, we used immunofluorescence approaches to document the localization of various protein components of adherens junctions in relation to those that we have previously reported to occur at electrical synapses formed by neuronal gap junctions composed of connexin36 (Cx36). The adherens junction constituents N-cadherin and nectin-1 were frequently found to localize near or overlap with Cx36-containing gap junctions in several brain regions examined. This was also true of the adherens junction-associated proteins α-catenin and β-catenin, as well as the proteins zonula occludens-1 and AF6 (aka, afadin) that were reported constituents of both adherens junctions and gap junctions. The deployment of the protein constituents of these junctions was especially striking at somatic contacts between primary afferent neurons in the mesencephalic trigeminal nucleus (MesV), where the structural components of adherens junctions appeared to be maintained in connexin36 null mice. These results support emerging views concerning the multi-molecular composition of electrical synapses and raise possibilities for various structural and functional protein–protein interactions at what now can be considered the adherens junction–neuronal gap junction complex. Further, the results point to intracellular signaling pathways that could potentially contribute to the assembly, maintenance and turnover of this complex, as well as to the dynamic nature of neuronal communication at electrical synapses. [ABSTRACT FROM AUTHOR]

Gap junctions (GJs) were discovered more than five decades ago, and since that time enormous strides have been made in understanding their structure and function. Despite the voluminous literature concerning the function of GJs, the involvement of these membrane structures in the central mechanisms underlying oscillations and synchrony in the neuronal network is still a matter of intensive debate. This review summarizes what is known concerning the involvement of GJs as electrical synapses in mechanisms underlying the generation of theta band oscillations. The first part of the chapter discusses the role of GJs in mechanisms of oscillations and synchrony. Following this, in vitro , ex vivo , and in vivo experiments concerning the involvement of GJs in the generation of hippocampal formation theta in rats are reviewed. [ABSTRACT FROM AUTHOR]

Highlights: [•] Locus coeruleus gap junctions are important to CO2 respiratory response. [•] Gap junction blockade in the locus coeruleus attenuates the hypercapnic ventilatory response. [•] Electrical synapses in locus coeruleus neurons play a role in the CO2 drive to breathe. [ABSTRACT FROM AUTHOR]

How is the cerebellum capable of efficient motor learning and control despite very low firing of the inferior olive (IO) inputs, which are postulated to carry errors needed for learning and contribute to on-line motor control? IO neurons form the largest electrically coupled network in the adult human brain. Here, we discuss how intermediate coupling strengths can lead to chaotic resonance and increase information transmission of the error signal despite the very low IO firing rate. This increased information transmission can then lead to more efficient learning than with weak or strong coupling. In addition, we argue that a dynamic modulation of IO electrical coupling via the Purkinje cell-deep cerebellar neurons - IO triangle could speed up learning and improve on-line control. Initially strong coupling would allow transmission of large errors to multiple functionally related Purkinje cells, resulting in fast but coarse learning as well as significant effects on deep cerebellar nucleus and on-line motor control. In the late phase of learning decreased coupling would allow desynchronized IO firing, allowing high-fidelity transmission of error, resulting in slower but fine learning, and little on-line motor control effects. [ABSTRACT FROM AUTHOR]

Abstract: The term synapse applies to cellular specializations that articulate the processing of information within neural circuits by providing a mechanism for the transfer of information between two different neurons. There are two main modalities of synaptic transmission: chemical and electrical. While most efforts have been dedicated to the understanding of the properties and modifiability of chemical transmission, less is still known regarding the plastic properties of electrical synapses, whose structural correlate is the gap junction. A wealth of data indicates that, rather than passive intercellular channels, electrical synapses are more dynamic and modifiable than was generally perceived. This article will discuss the factors determining the strength of electrical transmission and review current evidence demonstrating its dynamic properties. Like their chemical counterparts, electrical synapses can also be plastic and modifiable. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions. [Copyright &y& Elsevier]

Abstract: Adaptation enables the visual system to operate across a large range of background light intensities. There is evidence that one component of this adaptation is mediated by modulation of gap junctions functioning as electrical synapses, thereby tuning and functionally optimizing specific retinal microcircuits and pathways. The AII amacrine cell is an interneuron found in most mammalian retinas and plays a crucial role for processing visual signals in starlight, twilight and daylight. AII amacrine cells are connected to each other by gap junctions, potentially serving as a substrate for signal averaging and noise reduction, and there is evidence that the strength of electrical coupling is modulated by the level of background light. Whereas there is extensive knowledge concerning the retinal microcircuits that involve the AII amacrine cell, it is less clear which signaling pathways and intracellular transduction mechanisms are involved in modulating the junctional conductance between electrically coupled AII amacrine cells. Here we review the current state of knowledge, with a focus on the recent evidence that suggests that the modulatory control involves activity-dependent changes in the phosphorylation of the gap junction channels between AII amacrine cells, potentially linked to their intracellular Ca2+ dynamics. This article is part of a Special Issue entitled Electrical Synapses. [Copyright &y& Elsevier]

Electrical synapses formed by gap junctions between neurons create networks of electrically coupled neurons in the mammalian brain, where these networks have been found to play important functional roles. In most cases, interneuronal gap junctions occur at remote dendro-dendritic contacts, making difficult accurate characterization of their physiological properties and correlation of these properties with their anatomical and morphological features of the gap junctions. In the mesencephalic trigeminal (MesV) nucleus where neurons are readily accessible for paired electrophysiological recordings in brain stem slices, our recent data indicate that electrical transmission between MesV neurons is mediated by connexin36 (Cx36)-containing gap junctions located at somato-somatic contacts. We here review evidence indicating that electrical transmission between these neurons is supported by a very small fraction of the gap junction channels present at cell-cell contacts. Acquisition of this evidence was enabled by the unprecedented experimental access of electrical synapses between MesV neurons, which allowed estimation of the average number of open channels mediating electrical coupling in relation to the average number of gap junction channels present at these contacts. Our results indicate that only a small proportion of channels (~0.1 %) appear to be conductive. On the basis of similarities with other preparations, we postulate that this phenomenon might constitute a general property of vertebrate electrical synapses, reflecting essential aspects of gap junction function and maintenance. [ABSTRACT FROM AUTHOR]

Abstract: Field potential signals, corresponding to electrographic seizures in cortical structures, often contain two components, which sometimes appear to be separable and other times to be superimposed. The first component consists of low-amplitude very fast oscillations (VFO, >70–80 Hz); the second component consists of larger amplitude transients, lasting tens to hundreds of ms, and variously called population spikes, EEG spikes, or bursts—terms chosen in part because of the cellular correlates of the field events. To first approximation, the two components arise because of distinctive types of cellular interactions: gap junctions for VFO (a model of which is reviewed in the following), and recurrent synaptic excitation and/or inhibition for the transients. With in vitro studies of epileptic human neocortical tissue, it is possible to elicit VFO alone, or VFO superimposed on a large transient, but not a large transient without the VFO. If such observations prove to be general, they would imply that gap junction-mediated interactions are the primary factor in epileptogenesis. It appears to be the case then, that in the setting of seizure initiation (but not necessarily under physiological conditions), the gain of gap junction-mediated circuits can actually be larger than the gain in excitatory synaptic circuits. [Copyright &y& Elsevier]

We consider a model network consisting of two identical neurons with inhibitory and electrical coupling and find conditions under which a particular type of coupling promotes stable in-phase locking, anti-phase behavior, or some other type of firing pattern. A traditional view is that fast inhibition leads to stable anti-phase behavior, while electrical coupling leads to stable in-phase locking. Here, we follow up with rigorous analysis our previous computational demonstration [T. Bem and J. Rinzel, J. Neurophysiol., 91 (2004), pp. 693--703] that this is not always the case. We give precise conditions, which depend on the intrinsic properties of the cells involved, for when this traditional view is not valid. In particular, if the cells have short duty cycles, then fast inhibitory coupling leads to an almost-in-phase solution in which short active phases of the two cells occur subsequently, one immediately after the other. Moreover, if the cells have short duty cycles, then a network with weak electrical coupling exhibits bistability of in-phase and anti-phase behavior. The cells are modeled as relaxation oscillators, and we analyze the network using geometric singular perturbation methods. This allows us to construct maps, fixed points of which correspond to a particular type of solution. Rigorous analysis of these maps leads to precise conditions for when a particular type of solution exists and when it is stable for either pure electrical or pure inhibitory coupling. We also demonstrate how adding the other type of coupling may change the network behavior. [ABSTRACT FROM AUTHOR]

Weak coupling theory is applied to a model for firing waves in the procerebral lobe of the slug. Inhibitory synapses and electrical synapses have different synchronizing properties. We show that, in concert, these two types of coupling can cause a bifurcation to a patterned state from synchrony which ultimately develops into traveling waves. Normal forms for the bifurcation are computed, and the results are compared to numerical simulations of the phase models. [ABSTRACT FROM AUTHOR]

Sensitization of reflexive shortening in the leech has been linked to serotonin (5-HT)-induced changes in the excitability of a single interneuron, the S cell. This neuron is necessary for sensitization and complete dishabituation of reflexive shortening, during which it contributes to the sensory-motor reflex. The S cell does not contain 5-HT, which is released primarily from the Retzius (R) cells, whose firing enhances S-cell excitability. Here, we show that the S cell excites the R cells, mainly via a fast disynaptic pathway in which the first synapse is the electrical junction between the S cell and the coupling interneurons, and the second synapse is a glutamatergic synapse of the coupling interneurons onto the R cells. The S cell-triggered excitatory postsynaptic potential in the R cell diminishes and nearly disappears in elevated concentrations of divalent cations because the coupling interneurons become inexcitable under these conditions. Serotonin released from the R cells feeds back on the S cell and increases its excitability by activating a 5-HT7-like receptor; 5-methoxytryptamine (5-MeOT; 10 µM) mimics the effects of 5-HT on S cell excitability, and effects of both 5-HT and 5-MeOT are blocked by pimozide (10 µM) and SB-269970 [(R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol] (5 µM). This feedback loop may be critical for the full expression of sensitization of reflexive shortening. [ABSTRACT FROM AUTHOR]

Synchronous activity is common in the neocortex, although its significance, mechanisms, and development are poorly understood. Previous work showed that networks of electrically coupled inhibitory interneurons called low-threshold spiking (LTS) cells can fire synchronously when stimulated by metabotropic glutamate receptors. Here we found that the coordinated inhibition emerging from an activated LTS network could induce correlated spiking patterns among neighboring excitatory cells. Synchronous activity among LTS cells was absent at postnatal day 12 (P12) but appeared abruptly over the next few days. The rapid development of the LTS-synchronizing system coincided with the maturation of the inhibitory outputs and intrinsic membrane properties of the neurons. In contrast, the incidence and magnitude of electrical synapses remained constant between P8 and P15. The developmental transformation of LTS interneurons into a synchronous, oscillatory network overlaps with the onset of active somatosensory exploration, suggesting a potential role for this synchronizing system in sensory processing. [ABSTRACT FROM AUTHOR]

Many neurons in the mammalian central nervous system communicate through electrical synapses, defined here as gap junction--mediated connections. Electrical synapses are reciprocal pathways for ionic current and small organic molecules. They are often strong enough to mediate close synchronization of subthreshold and spiking activity among clusters of neurons. The most thoroughly studied electrical synapses occur between excitatory projection neurons of the inferior olivary nucleus and between inhibitory interneurons of the neocortex, hippocampus, and thalamus. All these synapses require the gap junction protein connexin36 (Cx36) for robust electrical coupling. Cx36 appears to interconnect neurons exclusively, and it is expressed widely along the mammalian neuraxis, implying that there are undiscovered electrical synapses throughout the central nervous system. Some central neurons may be electrically coupled by other connexin types or by pannexins, a newly described family of gap junction proteins. Electrical synapses are a ubiquitous yet underappreciated feature of neural circuits in the mammalian brain. [ABSTRACT FROM AUTHOR]

Auditory afferents terminating as mixed, electrical, and chemical, synapses on the goldfish Mauthner cells constitute an ideal experimental model to study the properties of gap junctions in the nervous system as well as to explore possible functional interactions with the other major form of interneuronal communication--chemically mediated synapses. By combining confocal microscopy and freeze-fracture replica immunogold labeling (FRIL), we found that gap junctions at these synapses contain connexin35 (Cx35), the fish ortholog of the neuron-specific human and mouse connexin36 (Cx36). Conductance of gap junction channels at these endings is known to be dynamically modulated by the activity of their co-localized chemically mediated glutamatergic synapses. By using simultaneous pre- and postsynaptic recordings at these single terminals, we demonstrate that such functional interaction takes place in the same ending, within a few micrometers. Accordingly, we also found evidence by confocal and FRIL double-immunogold labeling that the NR1 subunit of the NMDA glutamate receptor, proposed to be a key regulatory element, is present at postsynaptic densities closely associated with gap junction plaques containing Cx35. Given the widespread distribution of Cx35- and Cx36-mediated electrical synapses and glutamatergic synapses, our data suggest that the local functional interactions observed at these identifiable junctions may also apply to other electrical synapses, including those in mammalian brain. [ABSTRACT FROM AUTHOR]

Simple Summary: Relevant brain functions, such as perception, organization of behavior, and cognitive processes, are the outcome of information processing by neural circuits. Within these circuits, communication between neurons mainly relies on two modalities of synaptic transmission: chemical and electrical. Moreover, changes in the strength of these connections, aka synaptic plasticity, are believed to underlie processes of learning and memory, and its dysfunction has been suggested to underlie a variety of neurological disorders. While the relevance of chemical transmission and its plastic changes are known in great detail, analogous mechanisms and functional impact of their electrical counterparts were only recently acknowledged. In this article, we review the basic physical principles behind electrical transmission between neurons, the plethora of functional operations supported by this modality of neuron-to-neuron communication, as well as the basic principles of plasticity at these synapses. 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. [ABSTRACT FROM AUTHOR]

The article focuses on a study related to activity-dependent plasticity of electrical synapses in the thalamic reticular nucleus (TRN) in calcium-dependent pathway by J. Sevetson and colleagues. Topics include long-term depression of electrical coupling (eLTD) at electrical synapses in TRN; requirement of calcium ion entry through T-type calcium channels for the induction of burst-induced eLTD; and blocking activation of the calcium-activated protein phosphatase calcineurin with FK-506.