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A significant component of the repetitive dynamics during locomotion in vertebrates is generated within the spinal cord. The legged locomotion of mammals is most likely controled by a hierarchical, multi-layer spinal network structure, while the axial circuitry generating the undulatory swimming motion of animals like lamprey is thought to have only a single layer in each segment. Recent experiments have suggested a hybrid network structure in zebrafish larvae in which two types of excitatory interneurons (V2a-I and V2a-II) both make first-order connections to the brain and last-order connections to the motor pool. These neurons are connected by electrical and chemical synapses across segments. Through computational modeling and an asymptotic perturbation approach we show that this interleaved interaction between the two neuron populations allows the spinal network to quickly establish the correct activation sequence of the segments when starting from random initial conditions and to reduce the dependence of the intersegmental phase difference (ISPD) of the oscillations on the swimming frequency. The latter reduces the frequency dependence of the waveform of the swimming motion. In the model the reduced frequency dependence is largely due to the different impact of chemical and electrical synapses on the ISPD and to the significant spike-frequency adaptation that has been observed experimentally in V2a-II neurons, but not in V2a-I neurons. Our model makes experimentally testable predictions and points to a benefit of the hybrid structure for undulatory locomotion that may not be relevant for legged locomotion.

SummaryThe coordination of activity between brain cells is a key determinant of neural circuit function; nevertheless, approaches that selectively regulate communication between two distinct cellular components of a mammalian circuit remain sparse. To address this gap, we developed a novel class of gap junctions by selectively engineering two connexin proteins found inMorone americana(white perch fish): connexin34.7 (Cx34.7) and connexin35 (Cx35). By iteratively exploiting protein mutagenesis, a novelin vitroassay of connexin docking, and computational modeling of connexin hemichannel interactions, we uncovered a pattern of structural motifs that contribute to hemichannel docking compatibility. Targeting these motifs, we designed Cx34.7 and Cx35 hemichannels that dock with each other, but not with themselves, nor with other major connexins expressed in the mammalian central nervous system. We validated these hemichannelsin vivousingC. elegansand mice, demonstrating that they can facilitate communication across neural circuits composed of pairs of distinct cell types and modify behavior accordingly. Thus, we establish a potentially translational approach, ‘Long-termintegration ofCircuits using connexins’ (LinCx), for context-precise circuit-editing with unprecedented spatiotemporal specificity in mammals.

Rhythmically active neural circuits often contain reciprocally inhibitory modules that act as half-center oscillators. In half-center oscillators, alternating burst discharges require a mechanism to transition activity from one phase to the next, which requires particular synaptic and membrane properties. Here we found that active membrane properties of specific neurons and the temporal dynamics of particular synapses both contribute to the production of a stable rhythmic motor pattern in the swim central pattern generator (CPG) of the nudibranch mollusc, Dendronotus iris. This CPG is composed of only four neurons that are organized into two competing modules of a half-center oscillator. Each module is composed of a Swim Interneuron 2 (Si2) and the contralateral Swim Interneuron 3 (Si3). Si2 and Si3 each inhibit their own contralateral counterparts; however, the S2 contralateral synapses have a more negative reversal potential, making them more effective at hyperpolarizing the Si2 and the electrically coupled Si3 of the other module. Si3 rebounds first from inhibition due to a hyperpolarization-activated slow inward current. Si3 excites the Si2 in its module through both chemical and electrical synapses. An Si2-evoked slow inhibitory synaptic potential in Si3 suppresses its firing, terminating the burst generated by the module. Using dynamic clamping, we showed that the magnitude of the slow inhibition sets the periodicity of the oscillator. Thus, the network-driven oscillation is produced by each module rebounding from inhibition, maintaining the burst through self-excitation, and then terminating its burst through a buildup of slow synaptic inhibition, thereby releasing the other module from inhibition.

Electrical synapses couple inhibitory neurons across the brain, underlying a variety of functions that are modifiable by activity. Despite recent advances, many basic functions and contributions of electrical synapses within neural circuitry remain underappreciated. Among these is the source and impact of electrical synapse asymmetry. Using multi-compartmental models of neurons coupled through dendritic electrical synapses, we investigated intrinsic factors that contribute to synaptic asymmetry and that result in modulation of spike time between coupled cells. We show that electrical synapse location along a dendrite, input resistance, internal dendritic resistance, or directional conduction of the electrical synapse itself each alter asymmetry as measured by coupling between cell somas. Conversely, true synapse asymmetry can be masked by each of these properties. Furthermore, we show that asymmetry alters the spiking timing and latency of coupled cells by up to tens of milliseconds, depending on direction of conduction or dendritic location of the electrical synapse. These simulations illustrate that causes of asymmetry are multifactorial, may not be apparent in somatic measurements of electrical coupling, influence dendritic processing, and produce a variety of outcomes on spike timing of coupled cells. Our findings highlight aspects of electrical synapses that should be considered in experimental demonstrations of coupling, and when assembling networks containing electrical synapses.

Neuronal culture was used to investigate neuronal function in physiological and pathological conditions. Despite its inevitability, primary neuronal culture remained a gold standard method that requires laborious preparation, intensive training, and animal resources. To circumvent the shortfalls of primary neuronal preparations and efficiently give rise to functional neurons, we combine a neural stem cell culture method with a direct cell type-conversion approach. The lucidity of this method enables the efficient preparation of functional neurons from mouse neural progenitor cells on demand. We demonstrate that induced neurons (NPC-iNs) by this method make synaptic connections, elicit neuronal activity-dependent cellular responses, and develop functional neuronal networks. This method will provide a concise platform for functional neuronal assessments. This indeed offers a perspective for using these characterized neuronal networks for investigating plasticity mechanisms, drug screening assays, and probing the molecular and biophysical basis of neurodevelopmental and neurodegenerative diseases.

Peristalsis, the coordinated contraction—relaxation of the muscles of the stomach is important for normal gastric motility and is impaired in motility disorders. Coordinated electrical depolarizations that originate and propagate within a network of interconnected layers of interstitial cells of Cajal (ICC) and smooth muscle (SM) cells of the stomach wall as a slow-wave, underly peristalsis. Normally, the gastric slow-wave oscillates with a single period and uniform rostrocaudal lag, exhibiting network entrainment. Understanding of the integrative role of neurotransmission and intercellular coupling in the propagation of an entrained gastric slow-wave, important for understanding motility disorders, however, remains incomplete. Using a computational framework constituted of a novel gastric motility network (GMN) model we address the hypothesis that engaging biological oscillators (i.e., ICCs) by constitutive gap junction coupling mechanisms and enteric neural innervation activated signals can confer a robust entrained gastric slow-wave. We demonstrate that while a decreasing enteric neural innervation gradient that modulates the intracellular IP3 concentration in the ICCs can guide the aboral slow-wave propagation essential for peristalsis, engaging ICCs by recruiting the exchange of second messengers (inositol trisphosphate (IP3) and Ca2+) ensures a robust entrained longitudinal slow-wave, even in the presence of biological variability in electrical coupling strengths. Our GMN with the distinct intercellular coupling in conjunction with the intracellular feedback pathways and a rostrocaudal enteric neural innervation gradient allows gastric slow waves to oscillate with a moderate range of frequencies and to propagate with a broad range of velocities, thus preventing decoupling observed in motility disorders. Overall, the findings provide a mechanistic explanation for the emergence of decoupled slow waves associated with motility impairments of the stomach, offer directions for future experiments and theoretical work, and can potentially aid in the design of new interventional pharmacological and neuromodulation device treatments for addressing gastric motility disorders., Author summary The coordinated contraction and relaxation of the muscles of the stomach, known as peristalsis is important for normal gastric motility and primarily governed by electrical depolarizations that originate and propagate within a network of interconnected layers of interstitial cells of Cajal (ICCs) and smooth muscle cells of the stomach wall as a slow-wave. Under normal conditions, a gastric slow-wave oscillates with a single period and uniform rostrocaudal lag, exhibiting network entrainment. However, the understanding of intrinsic and extrinsic mechanisms that ensure propagation of a robust entrained slow-wave remains incomplete. Here, using a computational framework, we show that in conjunction with an enteric neural innervation gradient along the rostrocaudal ICC chain, and intercellular electrical coupling, the intercellular exchange of inositol trisphosphate between ICCs prevents decoupling by extending the longitudinal entrainment range along the stomach wall, even when variability in intercellular coupling exists. The findings from our study indicate ways that ensure the rostrocaudal spread of a robust gastric slow-wave and provide a mechanistic explanation for the emergence of decoupled slow waves associated with motility impairments of the stomach.

Bio-inspired recipes are being introduced to artificial neural networks for the efficient processing of spatio-temporal tasks. Among them, Leaky Integrate and Fire (LIF) model is the most remarkable one thanks to its temporal processing capability, lightweight model structure, and well investigated direct training methods. However, most learnable LIF networks generally take neurons as independent individuals that communicate via chemical synapses, leaving electrical synapses all behind. On the contrary, it has been well investigated in biological neural networks that the inter-neuron electrical synapse takes a great effect on the coordination and synchronization of generating action potentials. In this work, we are engaged in modeling such electrical synapses in artificial LIF neurons, where membrane potentials propagate to neighbor neurons via convolution operations, and the refined neural model ECLIF is proposed. We then build deep networks using ECLIF and trained them using a back-propagation-through-time algorithm. We found that the proposed network has great accuracy improvement over traditional LIF on five datasets and achieves high accuracy on them. In conclusion, it reveals that the introduction of the electrical synapse is an important factor for achieving high accuracy on realistic spatio-temporal tasks.

Synchronous oscillations in neural populations are considered being controlled by inhibitory neurons. In the granular layer of the cerebellum, two major types of cells are excitatory granular cells (GCs) and inhibitory Golgi cells (GoCs). GC spatiotemporal dynamics, as the output of the granular layer, is highly regulated by GoCs. However, there are various types of inhibition implemented by GoCs. With inputs from mossy fibers, GCs and GoCs are reciprocally connected to exhibit different network motifs of synaptic connections. From the view of GCs, feedforward inhibition is expressed as the direct input from GoCs excited by mossy fibers, whereas feedback inhibition is from GoCs via GCs themselves. In addition, there are abundant gap junctions between GoCs showing another form of inhibition. It remains unclear how these diverse copies of inhibition regulate neural population oscillation changes. Leveraging a computational model of the granular layer network, we addressed this question to examine the emergence and modulation of network oscillation using different types of inhibition. We show that at the network level, feedback inhibition is crucial to generate neural oscillation. When short-term plasticity was equipped on GoC-GC synapses, oscillations were largely diminished. Robust oscillations can only appear with additional gap junctions. Moreover, there was a substantial level of cross-frequency coupling in oscillation dynamics. Such a coupling was adjusted and strengthened by GoCs through feedback inhibition. Taken together, our results suggest that the cooperation of distinct types of GoC inhibition plays an essential role in regulating synchronous oscillations of the GC population. With GCs as the sole output of the granular network, their oscillation dynamics could potentially enhance the computational capability of downstream neurons., Author summary Synchronous oscillation dynamics is one of the ubiquitous features of neural population. It is thought to be coordinated by inhibitory neurons. However, there are various types of inhibition conveyed by different network pathways in neural circuits. Feedforward inhibition is a pathway from external inputs to inhibitory neurons leading to excitatory neurons, whereas feedback inhibition is looped from excitatory neurons first and back to them via inhibition neurons. Moreover, gap junctions are frequently expressed between inhibitory neurons. It is far from clear that how neural synchronous oscillation dynamics is modulated by these different types of inhibition. Here we investigated this question using a computational model of the cerebellar granular layer network equipped with excitatory granular cells and inhibitory Golgi cells. We demonstrate that feedback inhibition is important to engender network oscillations, whereas gap junctions create robust oscillations. Further analysis of cross-frequency coupling between different frequency bands reveals that the coupling is regulated by Golgi cells through feedback inhibition. Together with current literature in research on the cerebellum, neural synchronous oscillation, and cross-frequency coupling, our results indicate that distinct types of inhibition could contribute to rich dynamics of the cerebellum and promote the cerebellum to play a functional character of cognition modulator in the communication with other brain areas.

Les patients souffrant de douleurs neuropathiques (DN) ont des sensations anormales de douleurs dues à un mauvais contrôle de la transmission des signaux de la douleur. Les neurones GABA, glycine et parvalbumine des cornes dorsales médullaires et épinières communiquent par des synapses électriques formées de jonctions communicantes constituées de connexine 36 (Cx36). Ces neurones auraient une fonction de portail, bloquant ou autorisant la transmission de la douleur au cerveau. Un dysfonctionnement dans ce mécanisme entraînerait des DN. Par conséquent, les auteurs de cet article ont voulu étudier le rôle de la méfloquine, un bloqueur de Cx36, et l’expression de Cx36 dans un modèle de DN obtenu par constriction chronique du nerf infraorbitaire (CCI-IoN) chez le rat. Cx36 est surexprimé spécifiquement dans les neurones GABA de la corne dorsale de la moelle épinière médullaire en conditions neuropathiques. La méfloquine a permis de diminuer l’allodynie mécanique chez les rats CCI-IoN. Ces résultats suggèrent que les jonctions communicantes qui contiennent la Cx36 sont impliquées dans l’allodynie mécanique des douleurs orofaciales en conditions neuropathiques. Cela suggère que les neurones GABA jouent un rôle important dans la perception de douleur et que de futures études sont nécessaires.

Chemical and electrical synapses shape the dynamics of neuronal networks. Numerous theoretical studies have investigated how each of these types of synapses contributes to the generation of neuronal oscillations, but their combined effect is less understood. This limitation is further magnified by the impossibility of traditional neuronal mean-field models - also known as firing rate models or firing rate equations - to account for electrical synapses. Here, we introduce a firing rate model that exactly describes the mean-field dynamics of heterogeneous populations of quadratic integrate-and-fire (QIF) neurons with both chemical and electrical synapses. The mathematical analysis of the firing rate model reveals a well-established bifurcation scenario for networks with chemical synapses, characterized by a codimension-2 cusp point and persistent states for strong recurrent excitatory coupling. The inclusion of electrical coupling generally implies neuronal synchrony by virtue of a supercritical Hopf bifurcation. This transforms the cusp scenario into a bifurcation scenario characterized by three codimension-2 points (cusp, Takens-Bogdanov, and saddle-node separatrix loop), which greatly reduces the possibility for persistent states. This is generic for heterogeneous QIF networks with both chemical and electrical couplings. Our results agree with several numerical studies on the dynamics of large networks of heterogeneous spiking neurons with electrical and chemical couplings. © 2019 American Physical Society.

Previously we have demonstrated that vagal nerve stimulation (VNS) is capable of inducing hippocampal formation (HPC) theta rhythm (Broncel et al., 2017). The neuronal substrate underlying this novel phenomenon is poorly known, though the cholinergic and GABAergic profile of VNS-induced theta rhythm in anesthetized rats has just recently been addressed (Broncel et al., 2018a, 2019). In this study we extended our earlier observation concerning the pharmacological profile of VNS-induced theta oscillations. Specifically, the purpose of the present study was to test the hypothesis that VNS-induced hippocampal theta rhythm could be modulated by local HPC gap junctions (GJs) transmission. Two GJs agents were used: carbenoxolone, nonspecific GJs blocker and trimethylamine, a nonspecific opener of GJs. Two basic parameters of theta rhythm were evaluated: frequency and power. It was demonstrated that carbenoxolone inhibits VNS-induced theta while trimethylamine facilities it. These observations indicate that HPC electrical coupling mediates the theta rhythm induced by vagal nerve stimulation.

The brain consists of many interconnected systems and subsystems that have unidirectional or bidirectional connectivities. In this paper, we consider a two-layer neuronal network with unidirectional interlayer connections to investigate the effects of one layer on the other one. Two one-dimensional ring networks with non-local couplings construct the two-layer network. The couplings are considered to be linear to describe the electrical synapses. At first, the independent layer, which is not affected by the other layer, is analysed. Different patterns such as synchronizations, non-stationary chimera state and imperfect synchronization are observed in such solo network. Then the two-layer network is investigated by varying three coupling strengths of intra-layer and inter-layer links. The results show that the first layer can change the behaviour of neurons in the second layer according to the values of coupling strengths. The interaction of the interlayer and intralayer couplings can also induce the emergence of imperfect chimera state, which was not observed in the monolayer network. These self-organized phenomena can have strong relations with brain functions and malfunctions.

Cell assemblies and central pattern generators (CPGs) are related types of neuronal networks: both consist of interacting groups of neurons whose collective activities lead to defined functional outputs. In the case of a cell assembly, the functional output may be interpreted as a representation of something in the world, external or internal; for a CPG, the output ‘drives’ an observable (i.e. motor) behavior. Electrical coupling, via gap junctions, is critical for the development of CPGs, as well as for their actual operation in the adult animal. Electrical coupling is also known to be important in the development of hippocampal and neocortical principal cell networks. We here argue that electrical coupling – in addition to chemical synapses – may therefore contribute to the formation of at least some cell assemblies in adult animals.

Electrical synapses represent a widespread modality of interneuronal communication in the mammalian brain. These contacts, by lowering the effectiveness of random or temporally uncorrelated inputs, endow circuits of coupled neurons with the ability to selectively respond to simultaneous depolarizations. This mechanism may support coincidence detection, a property involved in sensory perception, organization of motor outputs, and improvement signal-to-noise ratio. While the role of electrical coupling is well established, little is known about the contribution of the cellular excitability and its modulations to the susceptibility of groups of neurons to coincident inputs. Here, we obtained dual whole cell patch-clamp recordings of pairs of mesencephalic trigeminal (MesV) neurons in brainstem slices from rats to evaluate coincidence detection and its determinants. MesV neurons are primary afferents involved in the organization of orofacial behaviors whose cell bodies are electrically coupled mainly in pairs through soma-somatic gap junctions. We found that coincidence detection is highly heterogeneous across the population of coupled neurons. Furthermore, combined electrophysiological and modeling approaches reveal that this heterogeneity arises from the diversity of MesV neuron intrinsic excitability. Consistently, increasing these cells’ excitability by upregulating the hyperpolarization-activated cationic current ( IH) triggered by cGMP results in a dramatic enhancement of the susceptibility of coupled neurons to coincident inputs. In conclusion, the ability of coupled neurons to detect coincident inputs is critically shaped by their intrinsic electrophysiological properties, emphasizing the relevance of neuronal excitability for the many functional operations supported by electrical transmission in mammals.NEW & NOTEWORTHY We show that the susceptibility of pairs of coupled mesencephalic trigeminal (MesV) neurons to coincident inputs is highly heterogenous and depends on the interaction between electrical coupling and neuronal excitability. Additionally, upregulating the hyperpolarization-activated cationic current ( IH) by cGMP results in a dramatic increase of this susceptibility. The IHand electrical synapses have been shown to coexist in many neuronal populations, suggesting that modulation of this conductance could represent a common strategy to regulate circuit operation supported by electrical coupling.

We analyze single and coupled Hindmarsh-Rose neurons in the presence of a time varying electromagnetic field which results from the exchange of ions across the membrane. Memristors are used to model the relation between magnetic flux of the electromagnetic field and the membrane potential of interacting neurons. The bifurcation analysis of Hindmarsh-Rose neurons has been carried out by varying the modulation intensity of induced current on the membrane potential. Many important dynamical behaviors such as synchrony, desynchrony, amplitude death, anti-phase oscillations, coexistence of resting and spiking state, and near death rare spikes are observed when the neurons are coupled using electrical and chemical synapses. In all cases the transverse Lyapunov exponents are plotted to observe the point of transition from desynchrony to synchrony. The memristor based analysis on neural networks can contribute to biological system modeling and can be used as a synapse in hardware of artificial neural networks.

Experimental data published earlier confirming the representations of the reticular theory of the organization of the nervous system are analyzed. It is noted that Sherrington’s evidence has refuted the main concept of the neuronal theory of Ramon y Cajal, the law of dynamic polarization of neurons. After the detection of gap junctions (GJs), the adhesion of neurites, their high electrical and metabolic permeability, and their cumulative interaction were detected. Data demonstrating that GJs are able to transform into syncytial perforations are given, and somatic GJs, under favorable conditions, can convert neurons into dikaryons. It is assumed that all the phenomena described are consecutive stages of a single process of reconstruction of the outer cell membrane of the neuron.

Electrical synapses are found in vertebrate and invertebrate nervous systems. The cellular basis of these synapses is the gap junction, a group of intercellular channels that mediate direct communication between adjacent neurons. Similar to chemical synapses, electrical connections are modifiable and their variations in strength provide a mechanism for reconfiguring neural circuits. In addition, electrical synapses dynamically regulate neural circuits through properties without equivalence in chemical transmission. Because of their continuous nature and bidirectionality, electrical synapses allow electrical currents underlying changes in membrane potential to leak to ‘coupled’ partners, dampening neuronal excitability and altering their integrative properties. Remarkably, this effect can be transiently alleviated when comparable changes in membrane potential simultaneously occur in each of the coupled neurons, a phenomenon that is dynamically dictated by the timing of arriving signals such as synaptic potentials. By way of this mechanism, electrical synapses influence synaptic integration and action potential generation, imparting an additional layer of dynamic complexity to neural circuits. Electrical synapses comprise intercellular channels termed gap junctions and are found in vertebrate and invertebrate nervous systems. In this Review, Pepe Alcami and Alberto Pereda examine the properties of electrical synapses that influence neural circuit dynamics without modifying gap junction conductance.

The dorsal portion of the descending octaval nucleus (dDO), the main first-order auditory nucleus in jawed fish, includes four lateral and three medial neuronal populations that project to the auditory midbrain. One medial population and one lateral population contain neurons that receive a remarkably large axon terminal from the utricular branch of the octaval nerve. Immunocytochemistry for connexin 35 (Cx35) was used to determine whether this connection includes electrical synapses. Although Cx35 was not localized to these large contacts, it was observed in the three other lateral dDO populations. Another first-order nucleus, the dorsal portion of the anterior octaval nucleus (dAO), primitively projects to the auditory midbrain in jawed fishes and contains neurons positive for Cx35. Utricular branch terminals were coincident with some Cx35 puncta in dDO and dAO. The results are discussed in light of what is known about the occurrence of electrical synapses in first-order auditory and vestibular nuclei in fish and tetrapods.

The extracellular matrix (ECM) plays a key role in synaptogenesis and the regulation of synaptic functions in the central nervous system. Recent studies revealed that in addition to dopaminergic and serotoninergic neuromodulatory systems, microglia also contribute to the regulation of ECM remodeling. In the present work, we investigated the physiological role of microglia in the remodeling of perineuronal nets (PNNs), predominantly associated with parvalbumin-immunopositive (PV+) interneurons, and the perisynaptic ECM around pyramidal neurons in the hippocampus. Adult mice were treated with PLX3397 (pexidartinib), as the inhibitor of colony-stimulating factor 1 receptor (CSF1-R), to deplete microglia. Then, confocal analysis of the ECM and synapses was performed. Although the elimination of microglia did not alter the overall number or intensity of PNNs in the CA1 region of the hippocampus, it decreased the size of PNN holes and elevated the expression of the surrounding ECM. In the neuropil area in the CA1 str. radiatum, the depletion of microglia increased the expression of perisynaptic ECM proteoglycan brevican, which was accompanied by the elevated expression of presynaptic marker vGluT1 and the increased density of dendritic spines. Thus, microglia regulate the homeostasis of pre- and postsynaptic excitatory terminals and the surrounding perisynaptic ECM as well as the fine structure of PNNs enveloping perisomatic—predominantly GABAergic—synapses.

Electrical synapses are specialized structures that mediate the flow of electrical currents between neurons and have well known roles in synchronizing the activities of neuronal populations, both by mediating the current transfer from more active to less active neurons and by shunting currents from active neurons to their less active neighbors. However, how these positive and negative functions of electrical synapses are coordinated to shape rhythmic synaptic outputs and behavior is not well understood. Here, using a combination of genetics, behavioral analysis, and live calcium imaging in Caenorhabditis elegans, we show that electrical synapses formed by the gap junction protein INX-1/innexin couple the presynaptic terminals of a pair of motor neurons (AVL and DVB) to synchronize their activation in response to a pacemaker signal. Live calcium imaging reveals that inx-1/innexin mutations lead to asynchronous activation of AVL and DVB, due, in part, to loss of AVL-mediated activation of DVB by the pacemaker. In addition, loss of inx-1 leads to the ectopic activation of DVB at inappropriate times during the cycle through the activation of the L-type voltage-gated calcium channel EGL-19. We propose that electrical synapses between AVL and DVB presynaptic terminals function to ensure the precise and robust execution of a specific step in a rhythmic behavior by both synchronizing the activities of presynaptic terminals in response to pacemaker signaling and by inhibiting their activation in between cycles when pacemaker signaling is low.

Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. To our surprise, reducing dNRXN3 function in glia was sufficient to improve the phenotype of flies expressing mHTT in neurons, suggesting that mHTT's toxic effects in glia ramify throughout the brain. This supports a model in which dampening synaptic function is protective because it attenuates the excitotoxicity that characterizes HD., eLife digest When a neuron dies, through injury or disease, the body loses all communication that passes through it. The brain compensates by rerouting the flow of information through other neurons in the network. Eventually, if the loss of neurons becomes too great, compensation becomes impossible. This process happens in Alzheimer's, Parkinson's, and Huntington's disease. In the case of Huntington's disease, the cause is mutation to a single gene known as huntingtin. The mutation is present in every cell in the body but causes particular damage to parts of the brain involved in mood, thinking and movement. Neurons and other cells respond to mutations in the huntingtin gene by turning the activities of other genes up or down, but it is not clear whether all of these changes contribute to the damage seen in Huntington's disease. In fact, it is possible that some of the changes are a result of the brain trying to protect itself. So far, most research on this subject has focused on neurons because the huntingtin gene plays a role in maintaining healthy neuronal connections. But, given that all cells carry the mutated gene, it is likely that other cells are also involved. The glia are a diverse group of cells that support the brain, providing care and sustenance to neurons. These cells have a known role in maintaining the connections between neurons and may also have play a role in either causing or correcting the damage seen in Huntington's disease. The aim of Onur et al. was to find out which genes are affected by having a mutant huntingtin gene in neurons or glia, and whether severity of Huntington’s disease improved or worsened when the activity of these genes changed. First, Onur et al. identified genes affected by mutant huntingtin by comparing healthy human brains to the brains of people with Huntington's disease. Repeating the same comparison in mice and fruit flies identified genes affected in the same way across all three species, revealing that, in Huntington's disease, the brain dials down glial cell genes involved in maintaining neuronal connections. To find out how these changes in gene activity affect disease severity and progression, Onur et al. manipulated the activity of each of the genes they had identified in fruit flies that carried mutant versions of huntingtin either in neurons, in glial cells or in both cell types. They then filmed the flies to see the effects of the manipulation on movement behaviors, which are affected by Huntington’s disease. This revealed that purposely lowering the activity of the glial genes involved in maintaining connections between neurons improved the symptoms of the disease, but only in flies who had mutant huntingtin in their glial cells. This indicates that the drop in activity of these genes observed in Huntington’s disease is the brain trying to protect itself. This work suggests that it is important to include glial cells in studies of neurological disorders. It also highlights the fact that changes in gene expression as a result of a disease are not always bad. Many alterations are compensatory, and try to either make up for or protect cells affected by the disease. Therefore, it may be important to consider whether drugs designed to treat a condition by changing levels of gene activity might undo some of the body's natural protection. Working out which changes drive disease and which changes are protective will be essential for designing effective treatments.

SUMMARYShank3 mutations contribute to intellectual disability. Because SHANK3 is a protein scaffold that helps organize the multiprotein network of the glutamatergic postsynaptic density (PSD), alterations in chemical synaptic transmission are implicated. Electrical synaptic transmission is a second form of synaptic transmission, enabled by intercellular channels comprised of connexin36 that support direct electrical communication among neurons, electrical brain rhythms, and neurocognitive states. Using multiplex proteomics, we report that two autism-related mutations of mouse Shank3 disrupt the glutamatergic PSD differently, but have in common the disruption of an association between NMDA-type glutamate-receptors (NMDARs) and connexin36. Mutation of Shank3 exons 13-16 most robustly dissociated connexin36 from NMDARs while impairing electrical synaptic transmission and the synchrony of an electrical rhythm in mouse inferior olive. We suggest that electrical synapses are a component of an “extended PSD” sensitive to Shank3 mutations that produce intellectual disability, at least in part, by impairing electrical synaptic transmission.

Gap junctions between neurons serve as electrical synapses, in addition to conducting metabolites and signaling molecules. During development, early-appearing gap junctions are thought to prefigure chemical synapses, which appear much later. We present evidence for this idea at a central, glutamatergic synapse and provide some mechanistic insights. Loss or reduction in the levels of the gap junction protein Gjd2b decreased the frequency of glutamatergic miniature excitatory postsynaptic currents (mEPSCs) in cerebellar Purkinje neurons (PNs) in larval zebrafish. Ultrastructural analysis in the molecular layer showed decreased synapse density. Further, mEPSCs had faster kinetics and larger amplitudes in mutant PNs, consistent with their stunted dendritic arbors. Time-lapse microscopy in wild-type and mutant PNs reveals that Gjd2b puncta promote the elongation of branches and that CaMKII may be a critical mediator of this process. These results demonstrate that Gjd2b-mediated gap junctions regulate glutamatergic synapse formation and dendritic elaboration in PNs.

Electrical synapses provide rapid, bidirectional communication in nervous systems, accomplishing tasks distinct from and complementary to chemical synapses. Here, we demonstrate an artificial electrical synapse based on second-order conductance transition (SOCT) in an Ag-based memristor for the first time. High-resolution transmission electron microscopy indicates that SOCT is mediated by the virtual silver electrode. Besides the conventional chemical synaptic behaviors, the biphasic plasticity of electrical synapses is well emulated by integrating the device with a photosensitive element to form an optical pre-processing unit (OPU), which contributes to the retinal neural circuitry and is adaptive to ambient illumination. By synergizing the OPU and spiking neural network (SNN), adaptive pattern recognition tasks are accomplished under different light and noise settings. This work not only contributes to the further completion of synaptic behaviour for hardware-level neuromorphic computing, but also potentially enables image pre-processing with light adaptation and noise suppression for adaptive visual recognition.

Shank3 mutations contribute to intellectual disability. Because SHANK3 is a protein scaffold that helps organize the multiprotein network of the glutamatergic postsynaptic density (PSD), alterations in chemical synaptic transmission are implicated. Electrical synaptic transmission is a second form of synaptic transmission, enabled by intercellular channels comprised of connexin36 that support direct electrical communication among neurons, electrical brain rhythms, and neurocognitive states. Using multiplex proteomics, we report that two autism-related mutations of mouse Shank3 disrupt the glutamatergic PSD differently, but have in common the disruption of an association between NMDA-type glutamate-receptors (NMDARs) and connexin36. Mutation of Shank3 exons 13-16 most robustly dissociated connexin36 from NMDARs while impairing electrical synaptic transmission and the synchrony of an electrical rhythm in mouse inferior olive. We suggest that electrical synapses are a component of an “extended PSD” sensitive to Shank3 mutations that produce intellectual disability, at least in part, by impairing electrical synaptic transmission.

The vertebrate retina, like most other brain regions, undergoes relatively slow alterations in neural signaling in response to gradual changes in physiological conditions (e.g., activity changes to rest), or in response to gradual changes in environmental conditions (e.g., day changes into night). As occurs elsewhere in the brain, the modulatory processes that mediate slow adaptation in the retina are driven by extrinsic signals (e.g., changes in ambient light level) and/or by intrinsic signals such as those of the circadian (24-h) clock in the retina. This review article describes and discusses the extrinsic and intrinsic modulatory processes that enable neural circuits in the retina to optimize their visual performance throughout day and night as the ambient light level changes by ~10 billion-fold. In the first synaptic layer of the retina, cone photoreceptor cells form gap junctions with rods and signal cone-bipolar and horizontal cells (HCs). Distinct extrinsic and intrinsic modulatory processes in this synaptic layer are mediated by long-range feedback of the neuromodulator dopamine. Dopamine is released by dopaminergic cells, interneurons whose cell bodies are located in the second synaptic layer of the retina. Distinct actions of dopamine modulate chemical and electrical synapses in day and night. The retinal circadian clock increases dopamine release in the day compared to night, activating high-affinity dopamine D4receptors on cones. This clock effect controls electrical synapses between rods and cones so that rod-cone electrical coupling is minimal in the day and robust at night. The increase in rod-cone coupling at night improves the signal-to-noise ratio and the reliability of very dim multi-photon light responses, thereby enhancing detection of large dim objects on moonless nights.Conversely, maintained (30 min) bright illumination in the day compared to maintained darkness releases sufficient dopamine to activate low-affinity dopamine D1receptors on cone-bipolar cell dendrites. This non-circadian light/dark adaptive process regulates the function of GABAAreceptors on ON-cone-bipolar cell dendrites so that the receptive field (RF) surround of the cells is strong following maintained bright illumination but minimal following maintained darkness. The increase in surround strength in the day following maintained bright illumination enhances the detection of edges and fine spatial details.

Embryogenesis, as well as regeneration, is increasingly recognized to be orchestrated by an interplay of transcriptional and bioelectric networks. Spatiotemporal patterns of resting potentials direct the size, shape, and locations of numerous organ primordia during patterning. These bioelectrical properties are established by the function of ion channels and pumps that set voltage potentials of individual cells, and gap junctions (electrical synapses) that enable physiological states to propagate across tissue networks. Functional experiments to probe the roles of bioelectrical states can be carried out by targeting endogenous ion channels during development. Here, we describe protocols, optimized for the highly tractable Xenopus laevis embryo, for molecular genetic targeting of ion channels and connexins based on CRISPR, and monitoring of resting potential states using voltage-sensing fluorescent dye. Similar strategies can be adapted to other model species.

Embryogenesis, as well as regeneration, is increasingly recognized to be orchestrated by an interplay of transcriptional and bioelectric networks. Spatiotemporal patterns of resting potentials direct the size, shape, and locations of numerous organ primordia during patterning. These bioelectrical properties are established by the function of ion channels and pumps that set voltage potentials of individual cells, and gap junctions (electrical synapses) that enable physiological states to propagate across tissue networks. Functional experiments to probe the roles of bioelectrical states can be carried out by targeting endogenous ion channels during development. Here, we describe protocols, optimized for the highly tractable Xenopus laevis embryo, for molecular genetic targeting of ion channels and connexins based on CRISPR, and monitoring of resting potential states using voltage-sensing fluorescent dye. Similar strategies can be adapted to other model species.

Electrical synaptic transmission relies on neuronal gap junctions containing channels constructed by Connexins. While at chemical synapses neurotransmitter-gated ion channels are critically supported by scaffolding proteins, it is unknown if channels at electrical synapses require similar scaffold support. Here, we investigated the functional relationship between neuronal Connexins and Zonula Occludens 1 (ZO1), an intracellular scaffolding protein localized to electrical synapses. Using model electrical synapses in zebrafish Mauthner cells, we demonstrated that ZO1 is required for robust synaptic Connexin localization, but Connexins are dispensable for ZO1 localization. Disrupting this hierarchical ZO1/Connexin relationship abolishes electrical transmission and disrupts Mauthner cell-initiated escape responses. We found that ZO1 is asymmetrically localized exclusively postsynaptically at neuronal contacts where it functions to assemble intercellular channels. Thus, forming functional neuronal gap junctions requires a postsynaptic scaffolding protein. The critical function of a scaffolding molecule reveals an unanticipated complexity of molecular and functional organization at electrical synapses., eLife digest Neurons ‘talk’ with each another at junctions called synapses, which can either be chemical or electrical. Communication across a chemical synapse involves a ‘sending’ neuron releasing chemicals that diffuse between the cells and subsequently bind to specialized receptors on the receiving neuron. These complex junctions involve a large number of well-studied molecular actors. Electrical synapses, on the other hand, are believed to be simpler. There, neurons are physically connected via channels formed of ‘connexin’ proteins, which allow electrically charged ions to flow between the cells. However, it is likely that other proteins help to create these structures. In particular, recent evidence shows that without a structurally supporting ‘scaffolding’ protein called ZO1, electrical synapses cannot form in the brain of a tiny freshwater fish known as zebrafish. As their name implies, scaffolding proteins help cells organize their internal structure, for example by anchoring other molecules to the cell membrane. By studying electrical synapses in zebrafish, Lasseigne, Echeverry, Ijaz, Michel et al. now show that these structures are more complex than previously assumed. In particular, the experiments reveal that ZO1 proteins are only present on one side of electrical synapses; despite their deceptively symmetrical anatomical organization, these junctions can be asymmetric, like their chemical cousins. The results also show that ZO1 must be present for connexins to gather at electrical synapses, whereas the converse is not true. This suggests that when a new electrical synapse forms, ZO1 moves into position first: it then recruits or stabilizes connexins to form the channels connecting the two cells. In many animals with a spine, electrical synapses account for about 20% of all neural junctions. Understanding how these structures form and work could help to find new treatments for disorders linked to impaired electrical synapses, such as epilepsy.

Electrical synapses are present in almost all organisms that have a nervous system. However, their brain-wide expression patterns and the full range of contributions to neural function are unknown in most species. Here, we first provide a light-microscopic, immunohistochemistry-based anatomical map of all innexin gap junction proteins-the building blocks of electrical synapses-in the central nervous system of Drosophila melanogaster. Of those innexin types that are expressed in the nervous system, some localize to glial cells, whereas others are predominantly expressed in neurons, with shakB being the most widely expressed neuronal innexin. We then focus on the function of shakB in VS/HS cells-a class of visual projection neurons-thereby uncovering an unexpected role for electrical synapses. Removing shakB from these neurons leads to spontaneous, cell-autonomous voltage and calcium oscillations, demonstrating that electrical synapses are required for these cells' intrinsic stability. Furthermore, we investigate the role of shakB-type electrical synapses in early visual processing. We find that the loss of shakB from the visual circuits upstream of VS/HS cells differentially impairs ON and OFF visual motion processing pathways but is not required for the computation of direction selectivity per se. Taken together, our study demonstrates that electrical synapses are widespread across the Drosophila nervous system and that they play essential roles in neuronal function and visual information processing.

The term “synapse” represents the junction between nerve cells. There are two major types of synapses namely chemical...