Active Synapses Research Articles

Transition and bifurcation mechanism of firing activities in memristor synapse-coupled Hindmarsh–Rose bi-neuron model

Memristor, especially the locally active one, is widely used in emulating the synapse-inspired activities in neural networks, in which the connection between memristor properties and neuronal electrical activities requires further investigation. In this paper, a bi-neuron model is constructed by bi-directionally connecting a locally active memristor between the membrane potentials of two deterministic 3D HR neuron models. Complex spiking/bursting firing activities and their transitions are disclosed under different memristor control parameters. The bifurcation mechanisms of the revealed synchronous and asynchronous firing activities are explored inside each individual neuron by taking the externally input state variables as modulation parameters. These results demonstrate the crucial effect of the locally active memristor synapse on firing activities of its coupled network. FPGA-based digital circuit experiment is finally performed to verify the numerical results. This research is beneficial to understanding, control and application of firing activities in neural networks.

Huanglian Jiedu decoction alleviates ischemia-induced cerebral injury in rats by mitigating NET formation and activiting GABAergic synapses.

Huanglian Jiedu decoction (HLJD) has been used to treat ischemic stroke in clinic. However, the detailed protective mechanisms of HLJD on ischemic stroke have yet to be elucidated. The aim of this study is to elucidate the underlying pharmacological mechanisms of HLJD based on the inhibition of neuroinflammation and the amelioration of nerve cell damage. A middle cerebral artery occlusion reperfusion (MCAO/R) model was established in rats and received HLJD treatment. Effects of HLJD on neurological function was assessed based on Bederson's score, postural reflex test and asymmetry score. 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining, Hematein and eosin (HE) and Nissl staining were used to observe the pathological changes in brain. Then, transcriptomics was used to screen the differential genes in brain tissue in MCAO/R model rats following HLJD intervention. Subsequently, the effects of HLJD on neutrophil extracellular trap (NET) formation-related neuroinflammation, gamma-aminobutyric acid (GABA)ergic synapse activation, nerve cell damage and proliferation were validated using immunofluorescence, western blot and enzyme-linked immunosorbent assay (ELISA). Our results showed that HLJD intervention reduced the Bederson's score, postural reflex test score and asymmetry score in MCAO/R model rats. Pathological staining indicated that HLJD treatment decreased the cerebral infarction area, mitigated neuronal damage and increased the numbers of Nissl bodies. Transcriptomics suggested that HLJD affected 435 genes in MCAO/R rats. Among them, several genes involving in NET formation and GABAergic synapses pathways were dysregulated. Subsequent experimental validation showed that HLJD reduced the MPO+CitH3+ positive expression area, reduced the protein expression of PAD4, p-P38/P38, p-ERK/ERK and decreased the levels of IL-1β, IL-6 and TNF-α, reversed the increase of Iba1+TLR4+, Iba1+p65+ and Iba1+NLRP3+ positive expression area in brain. Moreover, HLJD increased GABA levels, elevated the protein expression of GABRG1 and GAT3, decreased the TUNEL positive expression area and increased the Ki67 positive expression area in brain. HLJD intervention exerts a multifaceted positive impact on ischemia-induced cerebral injury in MCAO/R rats. This intervention effectively inhibits neuroinflammation by mitigating NET formation, and concurrently improves nerve cell damage and fosters nerve cell proliferation through activating GABAergic synapses.

Neuronal LRP4 directs the development, maturation and cytoskeletal organization of Drosophila peripheral synapses.

Synaptic development requires multiple signaling pathways to ensure successful connections. Transmembrane receptors are optimally positioned to connect the synapse and the rest of the neuron, often acting as synaptic organizers to synchronize downstream events. One such organizer, the LDL receptor-related protein LRP4, is a cell surface receptor that has been most well-studied postsynaptically at mammalian neuromuscular junctions. Recent work, however, identified emerging roles, but how LRP4 acts as a presynaptic organizer and the downstream mechanisms of LRP4 are not well understood. Here, we show that LRP4 functions presynaptically at Drosophila neuromuscular synapses, acting in motoneurons to instruct pre- and postsynaptic development. Loss of presynaptic LRP4 results in multiple defects, impairing active zone organization, synapse growth, physiological function, microtubule organization, synaptic ultrastructure and synapse maturation. We further demonstrate that LRP4 promotes most aspects of presynaptic development via a downstream SR-protein kinase, SRPK79D. These data demonstrate a function for presynaptic LRP4 as a peripheral synaptic organizer, highlight a downstream mechanism conserved with its CNS function in Drosophila, and underscore previously unappreciated but important developmental roles for LRP4 in cytoskeletal organization, synapse maturation and active zone organization.

Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression.

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.

Molecular Organization and Regulation of the Mammalian Synapse by the Post-Translational Modification SUMOylation.

Neurotransmission occurs within highly specialized compartments forming the active synapse where the complex organization and dynamics of the interactions are tightly orchestrated both in time and space. Post-translational modifications (PTMs) are central to these spatiotemporal regulations to ensure an efficient synaptic transmission. SUMOylation is a dynamic PTM that modulates the interactions between proteins and consequently regulates the conformation, the distribution and the trafficking of the SUMO-target proteins. SUMOylation plays a crucial role in synapse formation and stabilization, as well as in the regulation of synaptic transmission and plasticity. In this review, we summarize the molecular consequences of this protein modification in the structural organization and function of the mammalian synapse. We also outline novel activity-dependent regulation and consequences of the SUMO process and explore how this protein modification can functionally participate in the compartmentalization of both pre- and post-synaptic sites.

An n-type organic synaptic transistor with dopant-sensitive plasticity enables sensory-adaptive robotics

Sensory intelligence of biological depends on the activity of synapses, which promotes enormous research on artificial synapses and bio-inspired sensory systems. Here, we propose a strategy of increasing channel permeability with doping concentration to demonstrate for the first time the application of n-type organic synaptic transistors (OSTs) in neuromorphic sensory robotic system. The threshold voltage and operating current of the OST are dominated by the concentration of N-DMBI molecular to implement tunable and reliable plasticity. As a result, the N-DMBI-doped OST exhibits essential synaptic functions and persistent memory as the dopant increases within a certain range (≤7 wt%). We construct a neuromorphic sensory robotic system with sensorimotor functionality by combining the n-type OST with a flexible tactile sensor and a dexterous manipulator. The robotic system demonstrates sensory memory and adaption in response to tactile stimuli. We believe this work provides a novel resource for the development of advanced sensory-intelligence systems that have neuronal properties.

In silico analyses of the involvement of GPR55, CB1R and TRPV1: response to THC, contribution to temporal lobe epilepsy, structural modeling and updated evolution.

The endocannabinoid (eCB) system is named after the discovery that endogenous cannabinoids bind to the same receptors as the phytochemical compounds found in Cannabis. While endogenous cannabinoids include anandamide (AEA) and 2-arachidonoylglycerol (2-AG), exogenous phytocannabinoids include Δ-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds finely tune neurotransmission following synapse activation, via retrograde signaling that activates cannabinoid receptor 1 (CB1R) and/or transient receptor potential cation channel subfamily V member 1 (TRPV1). Recently, the eCB system has been linked to several neurological diseases, such as neuro-ocular abnormalities, pain insensitivity, migraine, epilepsy, addiction and neurodevelopmental disorders. In the current study, we aim to: (i) highlight a potential link between the eCB system and neurological disorders, (ii) assess if THC exposure alters the expression of eCB-related genes, and (iii) identify evolutionary-conserved residues in CB1R or TRPV1 in light of their function. To address this, we used several bioinformatic approaches, such as transcriptomic (Gene Expression Omnibus), protein-protein (STRING), phylogenic (BLASTP, MEGA) and structural (Phyre2, AutoDock, Vina, PyMol) analyzes. Using RNA sequencing datasets, we did not observe any dysregulation of eCB-related transcripts in major depressive disorders, bipolar disorder or schizophrenia in the anterior cingulate cortex, nucleus accumbens or dorsolateral striatum. Following in vivo THC exposure in adolescent mice, GPR55 was significantly upregulated in neurons from the ventral tegmental area, while other transcripts involved in the eCB system were not affected by THC exposure. Our results also suggest that THC likely induces neuroinflammation following in vitro application on mice microglia. Significant downregulation of TPRV1 occurred in the hippocampi of mice in which a model of temporal lobe epilepsy was induced, confirming previous observations. In addition, several transcriptomic dysregulations were observed in neurons of both epileptic mice and humans, which included transcripts involved in neuronal death. When scanning known interactions for transcripts involved in the eCB system (n = 12), we observed branching between the eCB system and neurophysiology, including proteins involved in the dopaminergic system. Our protein phylogenic analyzes revealed that CB1R forms a clade with CB2R, which is distinct from related paralogues such as sphingosine-1-phosphate, receptors, lysophosphatidic acid receptors and melanocortin receptors. As expected, several conserved residues were identified, which are crucial for CB1R receptor function. The anandamide-binding pocket seems to have appeared later in evolution. Similar results were observed for TRPV1, with conserved residues involved in receptor activation. The current study found that GPR55 is upregulated in neurons following THC exposure, while TRPV1 is downregulated in temporal lobe epilepsy. Caution is advised when interpreting the present results, as we have employed secondary analyzes. Common ancestors for CB1R and TRPV1 diverged from jawless vertebrates during the late Ordovician, 450 million years ago. Conserved residues are identified, which mediate crucial receptor functions.

A maximum of two readily releasable vesicles per docking site at a cerebellar single active zone synapse.

Recent research suggests that in central mammalian synapses, active zones contain several docking sites acting in parallel. Before release, one or several synaptic vesicles (SVs) are thought to bind to each docking site, forming the readily releasable pool (RRP). Determining the RRP size per docking site has important implications for short-term synaptic plasticity. Here, using mouse cerebellar slices, we take advantage of recently developed methods to count the number of released SVs at single glutamatergic synapses in response to trains of action potentials (APs). In each recording, the number of docking sites was determined by fitting with a binomial model the number of released SVs in response to individual APs. After normalization with respect to the number of docking sites, the summed number of released SVs following a train of APs was used to estimate of the RRP size per docking site. To improve this estimate, various steps were taken to maximize the release probability of docked SVs, the occupancy of docking sites, as well as the extent of synaptic depression. Under these conditions, the RRP size reached a maximum value close to two SVs per docking site. The results indicate that each docking site contains two distinct SV-binding sites that can simultaneously accommodate up to one SV each. They further suggest that under special experimental conditions, as both sites are close to full occupancy, a maximal RRP size of two SVs per docking site can be reached. More generally, the results validate a sequential two-step docking model previously proposed at this preparation.

A maximum of two readily releasable vesicles per docking site at a cerebellar single active zone synapse

Recent research suggests that in central mammalian synapses, active zones contain several docking sites acting in parallel. Before release, one or several synaptic vesicles (SVs) are thought to bind to each docking site, forming the readily releasable pool (RRP). Determining the RRP size per docking site has important implications for short-term synaptic plasticity. Here, using mouse cerebellar slices, we take advantage of recently developed methods to count the number of released SVs at single glutamatergic synapses in response to trains of action potentials (APs). In each recording, the number of docking sites was determined by fitting with a binomial model the number of released SVs in response to individual APs. After normalization with respect to the number of docking sites, the summed number of released SVs following a train of APs was used to estimate of the RRP size per docking site. To improve this estimate, various steps were taken to maximize the release probability of docked SVs, the occupancy of docking sites, as well as the extent of synaptic depression. Under these conditions, the RRP size reached a maximum value close to two SVs per docking site. The results indicate that each docking site contains two distinct SV-binding sites that can simultaneously accommodate up to one SV each. They further suggest that under special experimental conditions, as both sites are close to full occupancy, a maximal RRP size of two SVs per docking site can be reached. More generally, the results validate a sequential two-step docking model previously proposed at this preparation.

The transcriptomics profiling of blood CD4 and CD8 T-cells in narcolepsy type I.

Narcolepsy Type I (NT1) is a rare, life-long sleep disorder arising as a consequence of the extensive destruction of orexin-producing hypothalamic neurons. The mechanisms involved in the destruction of orexin neurons are not yet elucidated but the association of narcolepsy with environmental triggers and genetic susceptibility (strong association with the HLA, TCRs and other immunologically-relevant loci) implicates an immuno-pathological process. Several studies in animal models and on human samples have suggested that T-cells are the main pathogenic culprits. RNA sequencing was performed on four CD4 and CD8 T-cell subsets (naive, effector, effector memory and central memory) sorted by flow cytometry from peripheral blood mononuclear cells (PBMCs) of NT1 patients and HLA-matched healthy donors as well as (age- and sex-) matched individuals suffering from other sleep disorders (OSD). The RNAseq analysis was conducted by comparing the transcriptome of NT1 patients to that of healthy donors and other sleep disorder patients (collectively referred to as the non-narcolepsy controls) in order to identify NT1-specific genes and pathways. We determined NT1-specific differentially expressed genes, several of which are involved in tubulin arrangement found in CD4 (TBCB, CCT5, EML4, TPGS1, TPGS2) and CD8 (TTLL7) T cell subsets, which play a role in the immune synapse formation and TCR signaling. Furthermore, we identified genes (GZMB, LTB in CD4 T-cells and NLRP3, TRADD, IL6, CXCR1, FOXO3, FOXP3 in CD8 T-cells) and pathways involved in various aspects of inflammation and inflammatory response. More specifically, the inflammatory profile was identified in the "naive" subset of CD4 and CD8 T-cell. We identified NT1-specific differentially expressed genes, providing a cell-type and subset specific catalog describing their functions in T-cells as well as their potential involvement in NT1. Several genes and pathways identified are involved in the formation of the immune synapse and TCR activation as well as inflammation and the inflammatory response. An inflammatory transcriptomic profile was detected in both "naive" CD4 and CD8 T-cell subsets suggesting their possible involvement in the development or progression of the narcoleptic process.

Immune proteins C1q and CD47 may contribute to aberrant microglia-mediated synapse loss in the aging monkey brain that is associated with cognitive impairment.

Cognitive impairment in learning, memory, and executive function occurs in normal aging even in the absence of Alzheimer's disease (AD). While neurons do not degenerate in humans or monkeys free of AD, there are structural changes including synapse loss and dendritic atrophy, especially in the dorsolateral prefrontal cortex (dlPFC), and these correlate with cognitive age-related impairment. Developmental studies revealed activity-dependent neuronal properties that lead to synapse remodeling by microglia. Microglia-mediated phagocytosis that may eliminate synapses is regulated by immune "eat me" and "don't eat me" signaling proteins in an activity-dependent manner, so that less active synapses are eliminated. Whether this process contributes to age-related synapse loss remains unknown. The present study used a rhesus monkey model of normal aging to investigate the balance between the "eat me" signal, complement component C1q, and the "don't eat me" signal, transmembrane glycoprotein CD47, relative to age-related synapse loss in dlPFC Area 46. Results showed an age-related elevation of C1q and reduction of CD47 at PSD95+ synapses that is associated with cognitive impairment. Additionally, reduced neuronal CD47 RNA expression was found, indicating that aged neurons were less able to produce the protective signal CD47. Interestingly, microglia do not show the hypertrophic morphology indicative of phagocytic activity. These findings suggest that in the aging brain, changes in the balance of immunologic proteins give microglia instructions favoring synapse elimination of less active synapses, but this may occur by a process other than classic phagocytosis such as trogocytosis.

High-resolution analysis of bound Ca2+ in neurons and synapses.

Calcium (Ca2+) is a well-known second messenger in all cells, and is especially relevant for neuronal activity. Neuronal Ca2+ is found in different forms, with a minority being freely soluble in the cell and more than 99% being bound to proteins. Free Ca2+ has received much attention over the last few decades, but protein-bound Ca2+ has been difficult to analyze. Here, we introduce correlative fluorescence and nanoscale secondary ion mass spectrometry imaging as a tool to describe bound Ca2+ As expected, bound Ca2+ is ubiquitous. It does not correlate to free Ca2+ dynamics at the whole-neuron level, but does correlate significantly to the intensity of markers for GABAergic pre-synapse and glutamatergic post-synapses. In contrast, a negative correlation to pre-synaptic activity was observed, with lower levels of bound Ca2+ observed in the more active synapses. We conclude that bound Ca2+ may regulate neuronal activity and should receive more attention in the future.

A 22-pJ/spike 73-Mspikes/s 130k-compartment neural array transceiver with conductance-based synaptic and membrane dynamics.

Neuromorphic cognitive computing offers a bio-inspired means to approach the natural intelligence of biological neural systems in silicon integrated circuits. Typically, such circuits either reproduce biophysical neuronal dynamics in great detail as tools for computational neuroscience, or abstract away the biology by simplifying the functional forms of neural computation in large-scale systems for machine intelligence with high integration density and energy efficiency. Here we report a hybrid which offers biophysical realism in the emulation of multi-compartmental neuronal network dynamics at very large scale with high implementation efficiency, and yet with high flexibility in configuring the functional form and the network topology. The integrate-and-fire array transceiver (IFAT) chip emulates the continuous-time analog membrane dynamics of 65 k two-compartment neurons with conductance-based synapses. Fired action potentials are registered as address-event encoded output spikes, while the four types of synapses coupling to each neuron are activated by address-event decoded input spikes for fully reconfigurable synaptic connectivity, facilitating virtual wiring as implemented by routing address-event spikes externally through synaptic routing table. Peak conductance strength of synapse activation specified by the address-event input spans three decades of dynamic range, digitally controlled by pulse width and amplitude modulation (PWAM) of the drive voltage activating the log-domain linear synapse circuit. Two nested levels of micro-pipelining in the IFAT architecture improve both throughput and efficiency of synaptic input. This two-tier micro-pipelining results in a measured sustained peak throughput of 73 Mspikes/s and overall chip-level energy efficiency of 22 pJ/spike. Non-uniformity in digitally encoded synapse strength due to analog mismatch is mitigated through single-point digital offset calibration. Combined with the flexibly layered and recurrent synaptic connectivity provided by hierarchical address-event routing of registered spike events through external memory, the IFAT lends itself to efficient large-scale emulation of general biophysical spiking neural networks, as well as rate-based mapping of rectified linear unit (ReLU) neural activations.

Collective dynamics of a coupled Hindmarsh–Rose neurons with locally active memristor

A Locally active memristors can mimic neural synapses, resulting in rich neuro-morphological dynamics in biological neurons. To illustrate the impact of a local active memristive synapse, we consider coupled Hindmarsh–Rose (HR) neurons. Firstly, the dynamical transitions of the proposed system are investigated using bifurcation analysis and Lyapunov exponents, and we find that the transition between periodic and chaotic states depends on the input currents and memristive coupling strength. By performing the two-parameter analysis, the existence of periodic and chaotic regions is revealed. The collective behavior is then examined by expanding the network to include memristive coupled HR neurons under different network connectivities. We show that the system achieves synchronization behavior for all network connectivities, including regular, random, and small-world, when the strength of the memristive coupling is increased.

The influence of synaptic pathways on the synchronization patterns of regularly structured mChialvo map network

Synchronization of interconnecting units is one of the hottest topics many researchers are interested in. In addition, this emerging phenomenon is responsible for many biological processes, and thus, the synchronization of interacting neurons is an important field of study in neuroscience. Employing the memristive Chialvo (mChialvo) neuron map, this paper investigates the effect of electrical, inner-linking, chemical, and hybrid coupling functions on the synchronization state of a neuronal network with regular structure. Master stability function (MSF) analysis is performed to obtain the necessary conditions for synchronizing the built networks. Afterward, the MSF-based results are confirmed by calculating the synchronization error. Besides, the dynamics of the synchronous neurons are discussed based on the bifurcation analysis. Our results suggest that, compared to the electrical and inner-linking functions, chemical synapses facilitate mChialvo neurons’ synchronization since the neurons can achieve synchrony with a negligible chemical coupling strength. Further studies reveal that based on the active synapses, coupled mChialvo neurons can reach cluster synchronization, chimera state, sine-like synchronization, phase synchronization, and cluster phase synchronization.

Chronic inhibition of astrocytic aquaporin-4 induces autistic-like behavior in control rat offspring similar to maternal exposure to valproic acid

Social communication and interaction deficits, memory impairment, and anxiety-like behavior are characterized in many people identified with autism spectrum disorder (ASD). A thorough understanding of the specific aspects that contribute to the deficiencies associated with ASD can aid research into the etiology of the disorder while also providing targets for more effective intervention. As part of the ASD pathophysiology, alterations in synaptogenesis and abnormal network connections were seen in high-order brain areas, which control social behavior and communication. The early emergence of microglia during nervous system development may contribute to synaptic dysfunction and the pathobiology of ASD. Since aquaporin-4 (AQP4) appears to be required for the basic procedures of synapse activation, certain behavioral and cognitive impairments as well as disturbance in water homeostasis might likely arise from AQP4 deficiency. Here, through the measurement of the water content of the hippocampus and behavioral experiments we aim to explore the contribution of astrocytic AQP4 to the autism-like behavior induced by prenatal valproic acid (VPA) exposure and whether inhibition of AQP4 per se can induce autistic-like behavior in control rats.Microinjection of TGN-020 (10 µM, i.c.v), a specific AQP4 inhibitor, for 7 successive days before behavioral tasks from postnatal day 28 to 35 revealed that inhibition of AQP4 in the control offspring caused lower social interaction and locomotor activity, higher anxiety, and decreased ability to recognize novel objects, very similar to the behavioral changes observed in offspring prenatally exposed to VPA. However, VPA-exposed offspring treated with TGN-020, showed no further remarkable behavioral impairments than those detected in the autistic-like rats. Furthermore, both control offspring treated with TGN-020 and offspring exposed to VPA had a considerable accumulation of water in their hippocampi. But AQP4 inhibition did not affect the water status of the autistic-like rats.The findings of this study revealed that control offspring exhibited similar hippocampal water retention and behavioral impairments that were observed in maternal VPA-exposed offspring following inhibition of astrocytic AQP4, whereas, in autistic-like rats, it did not produce any significant change in water content and behaviors. Findings suggest that AQP4 deficiency could be associated with autistic disorder and may be a potential pharmaceutical target for treating autism in the future.

Asymmetric Voltage Attenuation in Dendrites Can Enable Hierarchical Heterosynaptic Plasticity.

Long-term synaptic plasticity is mediated via cytosolic calcium concentrations ([Ca2+]). Using a synaptic model that implements calcium-based long-term plasticity via two sources of Ca2+ - NMDA receptors and voltage-gated calcium channels (VGCCs) - we show in dendritic cable simulations that the interplay between these two calcium sources can result in a diverse array of heterosynaptic effects. When spatially clustered synaptic input produces a local NMDA spike, the resulting dendritic depolarization can activate VGCCs at nonactivated spines, resulting in heterosynaptic plasticity. NMDA spike activation at a given dendritic location will tend to depolarize dendritic regions that are located distally to the input site more than dendritic sites that are proximal to it. This asymmetry can produce a hierarchical effect in branching dendrites, where an NMDA spike at a proximal branch can induce heterosynaptic plasticity primarily at branches that are distal to it. We also explored how simultaneously activated synaptic clusters located at different dendritic locations synergistically affect the plasticity at the active synapses, as well as the heterosynaptic plasticity of an inactive synapse "sandwiched" between them. We conclude that the inherent electrical asymmetry of dendritic trees enables sophisticated schemes for spatially targeted supervision of heterosynaptic plasticity.

Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation

Alcohol is among the most widely consumed dietary substances. Excessive alcohol consumption damages the liver, heart, and brain. Alcohol also has strong immunoregulatory properties. Here, we report how alcohol impairs Tcell function via acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Upon alcohol consumption, acetate, the metabolite of alcohol, accumulates in lymphoid organs. Tcells exposed to acetate, exhibit increased acetylation of cortactin. Acetylation of cortactin inhibits filamentous actin binding and hence reduces Tcell migration, immune synapse formation and activation. While mutated, acetylation-resistant cortactin rescues the acetate-induced inhibition of Tcell migration, primary mouse cortactin knockout Tcells exhibited impaired migration. Acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in Tcells invitro and invivo in an influenza infection model in mice. Together these findings reveal cortactin as a possible target for mitigation of Tcell driven autoimmune diseases.

A missense mutation in RRM1 contributes to animal tameness.

The increased tameness to reduce avoidance of human in wild animals has been long proposed as the key step of animal domestication. The tameness is a complex behavior trait and largely determined by genetic factors. However, the underlying genetic mutations remain vague and how they influence the animal behaviors is yet to be explored. Behavior tests of a wild-domestic hybrid goat population indicate the locus under strongest artificial selection during domestication may exert a huge effect on the flight distance. Within this locus, only one missense mutation RRM1I241V which was present in the early domestic goat ~6500 years ago. Genome editing of RRM1I241V in mice showed increased tameness and sociability and reduced anxiety. These behavioral changes induced by RRM1I241V were modulated by the alternation of activity of glutamatergic synapse and some other synapse-related pathways. This study established a link between RRM1I241V and tameness, demonstrating that the complex behavioral change can be achieved by mutations under strong selection during animal domestication.

Hippocampal Proteomics Reveals the Role of Glutamatergic Synapse Activation in the Depression Induced by Perfluorooctane Sulfonate

Perfluorooctane sulfonate (PFOS), a new type of persistent organic pollutant in the environment of water, has drawn significant attention in recent years due to its widespread prevalence and high toxicity. Neurotoxicity is regarded as one of the major toxic effects of PFOS, while research studies on PFOS-induced depression and the underlying mechanisms remain scarce. In this study, behavioral tests revealed the depressive-like behaviors in PFOS-exposed male mice. Neuron damages including pyknosis and staining deepening were identified through hematoxylin and eosin staining. Then, we noticed the elevation of glutamate and proline levels as well as the decline of glutamine and tryptophan levels. Proteomics analysis identified 105 differentially expressed proteins that change in a dose-dependent manner and revealed that PFOS exposure activated the glutamatergic synapse signaling pathway, which were further confirmed by Western blot, and the data were consistent with the findings of the proteomics analysis. Additionally, the downstream signaling cyclic AMP-responsive element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) and synaptic plasticity-related postsynaptic density protein 95, synaptophysin, were downregulated. Our results highlight that PFOS exposure may inhibit the synaptic plasticity of the hippocampus via glutamatergic synapse and the CREB/BDNF signaling pathway to cause depressive-like behaviors in male mice.