Electrical Synapses Research Articles

PTEN Expression Regulates Gap Junction Connectivity in the Retina.

Manipulation of the phosphatase and tensin homolog (PTEN) pathway has been suggested as a therapeutic approach to treat or prevent vision loss due to retinal disease. In this study, we investigated the effects of deleting one copy of Pten in a well-characterized class of retinal ganglion cells called α-ganglion cells in the mouse retina. In Pten+/– retinas, α-ganglion cells did not exhibit major changes in their dendritic structure, although most cells developed a few, unusual loop-forming dendrites. By contrast, α-ganglion cells exhibited a significant decrease in heterologous and homologous gap junction mediated cell coupling with other retinal ganglion and amacrine cells. Additionally, the majority of OFF α-ganglion cells (12/18 cells) formed novel coupling to displaced amacrine cells. The number of connexin36 puncta, the predominant connexin that mediates gap junction communication at electrical synapses, was decreased by at least 50% on OFF α-ganglion cells. Reduced and incorrect gap junction connectivity of α-ganglion cells will affect their functional properties and alter visual image processing in the retina. The anomalous connectivity of retinal ganglion cells would potentially limit future therapeutic approaches involving manipulation of the Pten pathway for treating ganglion cell degeneration in diseases like glaucoma, traumatic brain injury, Parkinson’s, and Alzheimer’s diseases.

Dopamine-Mediated Circadian and Light/Dark-Adaptive Modulation of Chemical and Electrical Synapses in the Outer Retina.

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 D4 receptors 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 D1 receptors on cone-bipolar cell dendrites. This non-circadian light/dark adaptive process regulates the function of GABAA receptors 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.

Investigations of the functional role of connexin36 in sensory and sympathetic systems in adult mice

Electrical synapses formed by gap junctions composed of connexin36 (Cx36) occur between neurons in widespread areas of the mammalian central nervous system and enable neuron-to-neuron electrical coupling. We previously reported that dorsal root ganglia (DRG) sensory neurons containing transient receptor potential (TRP) channels, including TRPV1 and TRPM8, and those containing substance P in nociceptive DRG neurons express high levels of Cx36. It has also been reported that Cx36 is expressed in sympathetic preganglionic neurons (SPNs). Here we examined the functional roles of electrical synapses in primary afferent and SPN neural networks by using mice with global knockout (ko) of the Cx36 gene (Cx36 ko mice) and their wildtype (Wt) counterparts. Based on previous evidence showing that spinal neurons in Cx36 ko mice have attenuated responses to nociceptive stimulation when examined ex vivo; our hypothesis was that responses to nociceptive stimulation would be attenuated in vivo in intact Cx36 ko mice compared to Wt. To examine the role of coupling between DRG neurons, in vivo imaging was used to measure the fluorescence signal of Evans blue dye extravasation in skin of live animals after nociceptor activation. The extravasation levels relative to baseline fluorescence were 61.7±4% in Wt mice and 33.2±7% Cx36 ko mice (n=5 matched pairs, all males) after hind paw pinprick. Xylene applied topically on one of the ears induced more extravasation in the wt (255.4 ±3%) than in the Cx36 ko mice (204.6 ±1%). Using a fibre optic blood pressure monitoring system, we found that topical xylene application under isoflurane anesthesia changes the blood pressure, the heart rate, and the respiratory rate additionally to evoking the plasma extravasation. The attenuated extravasation response in the Cx36 ko mice suggests that electrical synapses known to occur between peripheral unmyelinated sensory fibers impact signal transmission from peripheral nerve endings and release other mediators that cause this response. To examine functional roles of coupling between SPNs, we compared physiological responses to colorectal distension (CRD) in Wt and Cx36 ko) mice in mice under isoflurane anesthesia. Mean arterial blood pressure during CRD increased to 108 ± 8% of baseline in Wt mice (n = 7), while this parameter did not change significantly in Cx36 ko mice (n = 12), but did show a tendency to decrease (to 97 ± 2%). Heart rate did not show significant changes, but we found that respiratory rate changes also occurred as part of the systemic response to CRD in both lines of mice. These data show differential regulation of sympathetic activity associated with electrical coupling between SPNs in Wt vs. Cx36 ko mice. In Wt mice with mid-thoracic complete spinal transection (n = 2), CRD also increased blood pressure when tested at 6-8 days after injury. The results taken together, point to the possibility that Cx36 in DRG and SPNs of adult mice has a significant functional role and warrant further research to understand how the presence of Cx36 in DRG and SPNs influences pain processing and associated autonomic responses.

Identification and classification of innexin gene transcripts in the central nervous system of the terrestrial slug Limax valentianus.

Intercellular gap junction channels and single-membrane channels have been reported to regulate electrical synapse and the brain function. Innexin is known as a gap junction-related protein in invertebrates and is involved in the formation of intercellular gap junction channels and single-cell membrane channels. Multiple isoforms of innexin protein in each species enable the precise regulation of channel function. In molluscan species, sequence information of innexins is still limited and the sequences of multiple innexin isoforms have not been classified. This study examined the innexin transcripts expressed in the central nervous system of the terrestrial slug Limax valentianus and identified 16 transcripts of 12 innexin isoforms, including the splicing variants. We performed phylogenetic analysis and classified the isoforms with other molluscan innexin sequences. Next, the phosphorylation, N-glycosylation, and S-nitrosylation sites were predicted to characterize the innexin isoforms. Further, we identified 16 circular RNA sequences of nine innexin isoforms in the central nervous system of Limax. The identification and classification of molluscan innexin isoforms provided novel insights for understanding the regulatory mechanism of innexin in this phylum.

Impacts of autapse on chaotic resonance in single neurons and small-world neuronal networks.

Chaotic resonance (CR) is a new phenomenon induced by an intermediate level of chaotic signal intensity in neuronal systems. In the current study, we investigated the effects of autapse on the CR phenomenon in single neurons and small-world (SW) neuronal networks. In single neurons, we assume that the neuron has only one autapse modelled as electrical, excitatory chemical and inhibitory chemical synapse, respectively. Then, we analysed the effects of each one on the CR, separately. Obtained results revealed that, regardless of its type, autapse significantly increases the chaotic resonance of the appropriate autaptic parameter's values. It is also observed that, at the optimal chaotic current intensity, the multiple CR emerges depending on autaptic time delay for all the autapse types when the autaptic delay time or its integer multiples match the half period or period of the weak signal. In SW networks, we investigated the effects of chaotic activity on the prorogation of pacemaker activity, where pacemaker neurons have different kinds of autapse as considered in single neuron cases. Obtained results revealed that excitatory and electrical autapses prominently increase the prorogation of pacemaker activity, whereas inhibitory autapse reduces or does not change it. Also, the best propagation was obtained when the autapse was excitatory. This article is part of the theme issue 'Vibrational and stochastic resonance in driven nonlinear systems (part 2)'.

Suppressing spiral waves in a lattice array of coupled neurons using delayed asymmetric synapse coupling

Abstract The coupling between neuronal oscillator plays a significant role in their network performance. When the coupling is asymmetric in an electrical synapse connection, the entire dynamical behaviour of the neuron model changes. Such asymmetric synapse coupling on neuron models exposed to magnetic flux induction will display more complex behaviours. Hence, we propose a coupled neuron model considering flux coupling with asymmetric electrical synapse. The various dynamical properties of the coupled neuron model are explored by considering the coupling coefficients and flux coupling constant as the control parameters. The coexistence of at least chaotic with chaotic or chaotic with periodic or periodic with periodic firing patterns are identified in the new model for different values of coupling strengths. Such coexisting firing patters are also seen for discrete values of the flux coupling coefficient. The investigation is expanded further to the network performance of such coupled neurons considering the coupling coefficient as the parameter of discussion. A simple applied plane wave is disturbed and rotating spiral waves are formed in the network for different values of the coupling strength. We have shown that by introducing magnetic flux coupling into the neuron model, we could suppress the spiral waves in the network. As an alternative by considering a coupled neuron model without flux coupling and with delayed asymmetric electrical synapse coupling, we showed that the spiral waves are completely suppressed effectively for selected values of delay. Using delayed coupling comparatively more effective than flux coupling for supressing spiral waves in the network.

The chemical brain hypothesis for the origin of nervous systems.

In nervous systems, there are two main modes of transmission for the propagation of activity between cells. Synaptic transmission relies on close contact at chemical or electrical synapses while volume transmission is mediated by diffusible chemical signals and does not require direct contact. It is possible to wire complex neuronal networks by both chemical and synaptic transmission. Both types of networks are ubiquitous in nervous systems, leading to the question which of the two appeared first in evolution. This paper explores a scenario where chemically organized cellular networks appeared before synapses in evolution, a possibility supported by the presence of complex peptidergic signalling in all animals except sponges. Small peptides are ideally suited to link up cells into chemical networks. They have unlimited diversity, high diffusivity and high copy numbers derived from repetitive precursors. But chemical signalling is diffusion limited and becomes inefficient in larger bodies. To overcome this, peptidergic cells may have developed projections and formed synaptically connected networks tiling body surfaces and displaying synchronized activity with pulsatile peptide release. The advent of circulatory systems and neurohemal organs further reduced the constraint imposed on chemical signalling by diffusion. This could have contributed to the explosive radiation of peptidergic signalling systems in stem bilaterians. Neurosecretory centres in extant nervous systems are still predominantly chemically wired and coexist with the synaptic brain.This article is part of the theme issue ‘Basal cognition: multicellularity, neurons and the cognitive lens’.

Recent Progress in Transistor‐Based Optoelectronic Synapses: From Neuromorphic Computing to Artificial Sensory System

Neuromorphic electronics draw attention as innovative approaches that facilitate hardware implementation of next‐generation artificial intelligent system including neuromorphic in‐memory computing, artificial sensory perception, and humanoid robotics. Among the various neuromorphic devices, optoelectronic synapses are promising neuromorphic devices that use optical means to mimic synaptic plasticity and related functions. Compared with classical neuromorphic chip based on electronic synapses using electrical means, photonic neuromorphic chip using light as input spike signal can be attractive alternative approach for next‐generation artificial intelligent system capable of high density, low power consumption, and low crosstalk. Thus, various optoelectronic synaptic electronics have been developed to overcome the drawback of conventional artificial intelligent system based on electrical synapses. Herein, the recent progresses in transistor‐based optoelectronic synapses for artificial intelligent system and review their device architecture, neuromorphic operational mechanisms, manufacturing methodologies, and advanced applications for artificial intelligent computing and visual perception systems are focused. Finally, the future challenges and research direction in the optoelectronic synaptic research are discussed.

Synchronization and chimera states in the network of electrochemically coupled memristive Rulkov neuron maps

Map-based neuronal models have received much attention due to their high speed, efficiency, flexibility, and simplicity. Therefore, they are suitable for investigating different dynamical behaviors in neuronal networks, which is one of the recent hottest topics. Recently, the memristive version of the Rulkov model, known as the m-Rulkov model, has been introduced. This paper investigates the network of the memristive version of the Rulkov neuron map to study the effect of the memristor on collective behaviors. Firstly, two m-Rulkov neuronal models are coupled in different cases, through electrical synapses, chemical synapses, and both electrical and chemical synapses. The results show that two electrically coupled memristive neurons can become synchronous, while the previous studies have shown that two non-memristive Rulkov neurons do not synchronize when they are coupled electrically. In contrast, chemical coupling does not lead to synchronization; instead, two neurons reach the same resting state. However, the presence of both types of couplings results in synchronization. The same investigations are carried out for a network of 100 m-Rulkov models locating in a ring topology. Different firing patterns, such as synchronization, lagged-phase synchronization, amplitude death, non-stationary chimera state, and traveling chimera state, are observed for various electrical and chemical coupling strengths. Furthermore, the synchronization of neurons in the electrical coupling relies on the network's size and disappears with increasing the nodes number.

<i>Shank3</i> Mutations Impair Electrical Synapse Scaffolding and Transmission in Mouse Brain

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.

Emulation of biphasic plasticity in retinal electrical synapses for light-adaptive pattern pre-processing.

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.

Rewiring Endogenous Bioelectric Circuits in the Xenopus laevis Embryo Model.

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.

Regulating synchronous patterns in neurons and networks via field coupling

Both electrical and chemical synapses play important role in receiving and propagating signals between biological neurons. The activation of electrical synapse coupling is generated via gap junction connection while chemical synapse coupling depends on the release of neurotransmitter for triggering stable propagation of ions. In a practical way, voltage coupling via resistor connection between artificial neural circuits is often used to describe the gap junction coupling via electrical synapse between neurons. Magnetic field coupling via induction coil between neural circuits can be effective to estimate the chemical synapse coupling when ions are propagated and released in the cell. In this paper, the physical properties of magnetic field coupling between neural circuits are discussed. For simplicity, two Hindmarsh–Rose neurons are connected to trigger magnetic field coupling and the coupling channel is tamed to detect possible occurrence of synchronization. Two neurons are stimulated with different stimuli, and it is confirmed that the synchronous firing mode is decided by the neuron with higher forcing amplitude. Furthermore, the collective behaviors of HR neuron in the small-world network and scale free network are investigated by changing the coupling intensity and diversity in external stimulus, respectively. Statistical synchronization factor is calculated to estimate the dependence of synchronization on coupling gain and the number of bursting neurons in the network. In case of small-world connection, synchronization approach becomes difficult. However, complete synchronization can be stabilized on the scale free network under magnetic field coupling.

Activity-dependent long-term potentiation of electrical synapses in the mammalian thalamus.

Activity-dependent changes of synapse strength have been extensively characterized at chemical synapses, but the relationship between physiological forms of activity and strength at electrical synapses remains poorly characterized and understood. For mammalian electrical synapses comprising hexamers of connexin36, physiological forms of neuronal activity in coupled pairs have thus far only been linked to long-term depression; activity that results in strengthening of electrical synapses has not yet been identified. Here, we performed dual whole-cell current-clamp recordings in acute slices of P11-P15 Sprague-Dawley rats of electrically coupled neurons of the thalamic reticular nucleus (TRN), a central brain area that regulates cortical input from and attention to the sensory surround. Using TTA-A2 to limit bursting, we show that tonic spiking in one neuron of a pair results in long-term potentiation of electrical synapses. We use experiments and computational modeling to show that the magnitude of plasticity expressed alters the functionality of the synapse. Potentiation is expressed asymmetrically, indicating that regulation of connectivity depends on the direction of use. Furthermore, calcium pharmacology and imaging indicate that potentiation depends on calcium flux. We thus propose a calcium-based activity rule for bidirectional plasticity of electrical synapse strength. Because electrical synapses dominate intra-TRN connectivity, these synapses and their activity-dependent modifications are key dynamic regulators of thalamic attention circuitry. More broadly, we speculate that bidirectional modifications of electrical synapses may be a widespread and powerful principle for ongoing, dynamic reorganization of neuronal circuitry across the brain.NEW & NOTEWORTHY This work reveals a physiologically relevant form of activity pairing in coupled neurons that results in long-term potentiation of mammalian electrical synapses. These findings, in combination with previous work, allow the authors to propose a bidirectional calcium-based rule for plasticity of electrical synapses, similar to those demonstrated for chemical synapses. These new insights inform the field on how electrical synapse plasticity may modify the neural circuits that incorporate them.

Phosphorylation of Connexin36 near the C-terminus switches binding affinities for PDZ-domain and 14\u20133\u20133 proteins in vitro

Connexin36 (Cx36) is the most abundant connexin in central nervous system neurons. It forms gap junction channels that act as electrical synapses. Similar to chemical synapses, Cx36-containing gap junctions undergo activity-dependent plasticity and complex regulation. Cx36 gap junctions represent multimolecular complexes and contain cytoskeletal, regulatory and scaffolding proteins, which regulate channel conductance, assembly and turnover. The amino acid sequence of mammalian Cx36 harbors a phosphorylation site for the Ca2+/calmodulin-dependent kinase II at serine 315. This regulatory site is homologous to the serine 298 in perch Cx35 and in close vicinity to a PDZ binding domain at the very C-terminal end of the protein. We hypothesized that this phosphorylation site may serve as a molecular switch, influencing the affinity of the PDZ binding domain for its binding partners. Protein microarray and pulldown experiments revealed that this is indeed the case: phosphorylation of serine 298 decreased the binding affinity for MUPP1, a known scaffolding partner of connexin36, and increased the binding affinity for two different 14–3–3 proteins. Although we did not find the same effect in cell culture experiments, our data suggest that phosphorylation of serine 315/298 may serve to recruit different proteins to connexin36/35-containing gap junctions in an activity-dependent manner.

Calmodulin Binding to Connexin 35: Specializations to Function as an Electrical Synapse.

Calmodulin binding is a nearly universal property of gap junction proteins, imparting a calcium-dependent uncoupling behavior that can serve in an emergency to decouple a stressed cell from its neighbors. However, gap junctions that function as electrical synapses within networks of neurons routinely encounter large fluctuations in local cytoplasmic calcium concentration; frequent uncoupling would be impractical and counterproductive. We have studied the properties and functional consequences of calmodulin binding to the electrical synapse protein Connexin 35 (Cx35 or gjd2b), homologous to mammalian Connexin 36 (Cx36 or gjd2). We find that specializations in Cx35 calmodulin binding sites make it relatively impervious to moderately high levels of cytoplasmic calcium. Calmodulin binding to a site in the C-terminus causes uncoupling when calcium reaches low micromolar concentrations, a behavior prevented by mutations that eliminate calmodulin binding. However, milder stimuli promote calcium/calmodulin-dependent protein kinase II activity that potentiates coupling without interference from calmodulin binding. A second calmodulin binding site in the end of the Cx35 cytoplasmic loop, homologous to a calmodulin binding site present in many connexins, binds calmodulin with very low affinity and stoichiometry. Together, the calmodulin binding sites cause Cx35 to uncouple only at extreme levels of intracellular calcium.

Optimal Self-Induced Stochastic Resonance in Multiplex Neural Networks: Electrical vs. Chemical Synapses.

Electrical and chemical synapses shape the dynamics of neural networks, and their functional roles in information processing have been a longstanding question in neurobiology. In this paper, we investigate the role of synapses on the optimization of the phenomenon of self-induced stochastic resonance in a delayed multiplex neural network by using analytical and numerical methods. We consider a two-layer multiplex network in which, at the intra-layer level, neurons are coupled either by electrical synapses or by inhibitory chemical synapses. For each isolated layer, computations indicate that weaker electrical and chemical synaptic couplings are better optimizers of self-induced stochastic resonance. In addition, regardless of the synaptic strengths, shorter electrical synaptic delays are found to be better optimizers of the phenomenon than shorter chemical synaptic delays, while longer chemical synaptic delays are better optimizers than longer electrical synaptic delays; in both cases, the poorer optimizers are, in fact, worst. It is found that electrical, inhibitory, or excitatory chemical multiplexing of the two layers having only electrical synapses at the intra-layer levels can each optimize the phenomenon. Additionally, only excitatory chemical multiplexing of the two layers having only inhibitory chemical synapses at the intra-layer levels can optimize the phenomenon. These results may guide experiments aimed at establishing or confirming to the mechanism of self-induced stochastic resonance in networks of artificial neural circuits as well as in real biological neural networks.

Genetic background mutations drive neural circuit hyperconnectivity in a fragile X syndrome model

BackgroundNeural circuits are initially assembled during development when neurons synapse with potential partners and later refined as appropriate connections stabilize into mature synapses while inappropriate contacts are eliminated. Disruptions to this synaptogenic process impair connectivity optimization and can cause neurodevelopmental disorders. Intellectual disability (ID) and autism spectrum disorder (ASD) are often characterized by synaptic overgrowth, with the maintenance of immature or inappropriate synapses. Such synaptogenic defects can occur through mutation of a single gene, such as fragile X mental retardation protein (FMRP) loss causing the neurodevelopmental disorder fragile X syndrome (FXS). FXS represents the leading heritable cause of ID and ASD, but many other genes that play roles in ID and ASD have yet to be identified.ResultsIn a Drosophila FXS disease model, one dfmr150M null mutant stock exhibits previously unreported axonal overgrowths at developmental and mature stages in the giant fiber (GF) escape circuit. These excess axon projections contain both chemical and electrical synapse markers, indicating mixed synaptic connections. Extensive analyses show these supernumerary synapses connect known GF circuit neurons, rather than new, inappropriate partners, indicating hyperconnectivity within the circuit. Despite the striking similarities to well-characterized FXS synaptic defects, this new GF circuit hyperconnectivity phenotype is driven by genetic background mutations in this dfmr150M stock. Similar GF circuit synaptic overgrowth is not observed in independent dfmr1 null alleles. Bulked segregant analysis (BSA) was combined with whole genome sequencing (WGS) to identify the quantitative trait loci (QTL) linked to neural circuit hyperconnectivity. The results reveal 8 QTL associated with inappropriate synapse formation and maintenance in the dfmr150M mutant background.ConclusionsSynaptogenesis is a complex, precisely orchestrated neurodevelopmental process with a large cohort of gene products coordinating the connectivity, synaptic strength, and excitatory/inhibitory balance between neuronal partners. This work identifies a number of genetic regions that contain mutations disrupting proper synaptogenesis within a particularly well-mapped neural circuit. These QTL regions contain potential new genes involved in synapse formation and refinement. Given the similarity of the synaptic overgrowth phenotype to known ID and ASD inherited conditions, identifying these genes should increase our understanding of these devastating neurodevelopmental disease states.

NMDAR-mediated modulation of gap junction circuit regulates olfactory learning in C. elegans

Modulation of gap junction-mediated electrical synapses is a common form of neural plasticity. However, the behavioral consequence of the modulation and the underlying molecular cellular mechanisms are not understood. Here, using a C. elegans circuit of interneurons that are connected by gap junctions, we show that modulation of the gap junctions facilitates olfactory learning. Learning experience weakens the gap junctions and induces a repulsive sensory response to the training odorants, which together decouple the responses of the interneurons to the training odorants to generate learned olfactory behavior. The weakening of the gap junctions results from downregulation of the abundance of a gap junction molecule, which is regulated by cell-autonomous function of the worm homologs of a NMDAR subunit and CaMKII. Thus, our findings identify the function of a gap junction modulation in an in vivo model of learning and a conserved regulatory pathway underlying the modulation.

Molecular basis of junctional current rectification at an electrical synapse.

Rectifying electrical synapses (RESs) exist across animal species, but their rectification mechanism is largely unknown. We investigated why RESs between AVA premotor interneurons and A-type cholinergic motoneurons (A-MNs) in Caenorhabditis elegans escape circuit conduct junctional currents (I j) only in the antidromic direction. These RESs consist of UNC-7 innexin in AVA and UNC-9 innexin in A-MNs. UNC-7 has multiple isoforms differing in the length and sequence of the amino terminus. In a heterologous expression system, only one UNC-7 isoform, UNC-7b, can form heterotypic gap junctions (GJs) with UNC-9 that strongly favor I j in the UNC-9 to UNC-7 direction. Knockout of unc-7b alone almost eliminated the I j, whereas AVA-specific expression of UNC-7b substantially rescued the coupling defect of unc-7 mutant. Neutralizing charged residues in UNC-7b amino terminus abolished the rectification property of UNC-7b/UNC-9 GJs. Our results suggest that the rectification property results from electrostatic interactions between charged residues in UNC-7b amino terminus.