Activation Of Postsynaptic Receptors Research Articles

Emerging Molecular and Synaptic Targets for the Management of Chronic Pain Caused by Systemic Lupus Erythematosus.

Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics. Understanding the molecular and synaptic mechanisms underlying abnormal neuronal activation along the pain signaling pathway is essential for developing new analgesics to address SLE-induced chronic pain. Recent studies, including those conducted by our team and others using the SLE animal model (MRL/lpr lupus-prone mice), have unveiled heightened excitability in nociceptive primary sensory neurons within the dorsal root ganglia and increased glutamatergic synaptic activity in spinal dorsal horn neurons, contributing to the development of chronic pain in mice with SLE. Nociceptive primary sensory neurons in lupus animals exhibit elevated resting membrane potentials, and reduced thresholds and rheobases of action potentials. These changes coincide with the elevated production of TNFα and IL-1β, as well as increased ERK activity in the dorsal root ganglion, coupled with decreased AMPK activity in the same region. Dysregulated AMPK activity is linked to heightened excitability in nociceptive sensory neurons in lupus animals. Additionally, the increased glutamatergic synaptic activity in the spinal dorsal horn in lupus mice with chronic pain is characterized by enhanced presynaptic glutamate release and postsynaptic AMPA receptor activation, alongside the reduced activity of glial glutamate transporters. These alterations are caused by the elevated activities of IL-1β, IL-18, CSF-1, and thrombin, and reduced AMPK activities in the dorsal horn. Furthermore, the pharmacological activation of spinal GPR109A receptors in microglia in lupus mice suppresses chronic pain by inhibiting p38 MAPK activity and the production of both IL-1β and IL-18, as well as reducing glutamatergic synaptic activity in the spinal dorsal horn. These findings collectively unveil crucial signaling molecular and synaptic targets for modulating abnormal neuronal activation in both the periphery and spinal dorsal horn, offering insights into the development of analgesics for managing SLE-induced chronic pain.

The neurobiological mechanisms and therapeutic prospect of extracellular ATP in depression.

Depression is a prevalent psychiatric disorder with high long-term morbidities, recurrences, and mortalities. Despite extensive research efforts spanning decades, the cellular and molecular mechanisms of depression remain largely unknown. What's more, about one third of patients do not have effective anti-depressant therapies, so there is an urgent need to uncover more mechanisms to guide the development of novel therapeutic strategies. Adenosine triphosphate (ATP) plays an important role in maintaining ion gradients essential for neuronal activities, as well as in the transport and release of neurotransmitters. Additionally, ATP could also participate in signaling pathways following the activation of postsynaptic receptors. By searching the website PubMed for articles about "ATP and depression" especially focusing on the role of extracellular ATP (eATP) in depression in the last 5 years, we found that numerous studies have implied that the insufficient ATP release from astrocytes could lead to depression and exogenous supply of eATP or endogenously stimulating the release of ATP from astrocytes could alleviate depression, highlighting the potential therapeutic role of eATP in alleviating depression. Currently, there are few reviews discussing the relationship between eATP and depression. Therefore, the aim of our review is to conclude the role of eATP in depression, especially focusing on the evidence and mechanisms of eATP in alleviating depression. We will provide insights into the prospects of leveraging eATP as a novel avenue for the treatment of depression.

A network pharmacology approach to reveal the key ingredients in Scrophulariae Radix (SR) and their effects against Alzheimer's disease

BackgroundScrophulariae Radix (SR) is a commonly used medicinal plant. Alzheimer's disease (AD) is a neurodegenerative disease for which there is no effective treatment. This study aims to initially clarify the potential mechanism of SR in the treatment of AD based on network pharmacology and molecular docking techniques. MethodsThe principal components and corresponding protein targets of SR were conducted by HPLC analysis and searched on TCMSP. AD targets were searched on DrugBank, Chemogenomics, TTD, OMIM and GeneCards databases. The compound-target network was constructed by Cytoscape3.8.2. The intersection of compound target and disease target was obtained and the coincidence target was imported into STRING database to construct a PPI network. We further performed GO and KEGG enrichment analysis on the targets. Meanwhile, molecular docking study and cell experiments were approved for the core target and the active compound. ResultsThrough multidatabase retrieval and integration, it was found that 17 components of SR could exert anti-AD effects against 40 targets. KEGG enrichment analysis indicated that Alzheimer's disease (hsa05010) was one of the most significant AD enrichment signalling pathways. Combined with the gene expression profile information in the AlzData database, 15 targets were found to be associated with tau or beta-amyloid protein (Aβ). GO analysis indicated that the primary molecular functions of SR in the treatment of AD were neurotransmitter receptor activity (GO:0007268), postsynaptic neurotransmitter receptor activity (GO:0070997), and acetylcholine receptor activity (GO:0050435). Moreover, we explored the anti-AD effects of SR extract and ursolic acid (UA) using SH-SY5Y cells. Treatment of SH-SY5Y cells with 20 μM UA significantly reduced the oxidative damage to these neuronal cells. ConclusionThis study reveals the active ingredients and potential molecular mechanism of SR in the treatment of AD, and provides a theoretical basis for further basic research and clinical application.

Impaired synaptic incorporation of AMPA receptors in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is the most common monogenetic cause of inherited intellectual disability and autism in humans. One of the well-characterized molecular phenotypes of Fmr1 KO mice, a model of FXS, is increased translation of synaptic proteins. Although this upregulation stabilizes in adulthood, abnormalities during the critical period of plasticity have long-term effects on circuit formation and synaptic properties. Using high-resolution quantitative proteomics of synaptoneurosomes isolated from the adult, developed brains of Fmr1 KO mice, we show a differential abundance of proteins regulating the postsynaptic receptor activity of glutamatergic synapses. We investigated the AMPA receptor composition and shuttling in adult Fmr1 KO and WT mice using a variety of complementary experimental strategies such as surface protein crosslinking, immunostaining of surface receptors, and electrophysiology. We discovered that the activity-dependent synaptic delivery of AMPARs is impaired in adult Fmr1 KO mice. Furthermore, we show that Fmr1 KO synaptic AMPARs contain more GluA2 subunits that can be interpreted as a switch in the synaptic AMPAR subtype toward an increased number of Ca2+-impermeable receptors in adult Fmr1 KO synapses.

(R,S)-trihexyphenidyl, acting via a muscarinic receptor-independent mechanism, inhibits hippocampal glutamatergic and GABAergic synaptic transmissions: Potential relevance for treatment of organophosphorus intoxication

Preclinical studies have reported that, compared to the muscarinic receptor (mAChR) antagonist atropine, (R,S)-trihexyphenidyl (THP) more effectively counters the cholinergic crisis, seizures, and neuropathology triggered by organophosphorus (OP)-induced acetylcholinesterase (AChE) inhibition. The greater effectiveness of THP was attributed to its ability to block mAChRs and N-methyl-d-aspartate-type glutamatergic receptors (NMDARs) in the brain. However, THP also inhibits α7 nicotinic receptors (nAChRs). The present study examined whether THP-induced inhibition of mAChRs, α7 nAChRs, and NMDARs is required to suppress glutamatergic synaptic transmission, whose overstimulation sustains OP-induced seizures. In primary hippocampal cultures, THP (1–30 μM) suppressed the frequency of excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs, respectively) recorded from neurons in nominally Mg2+-free solution. A single sigmoidal function adequately fit the overlapping concentration-response relationships for THP-induced suppression of IPSC and EPSC frequencies yielding an IC50 of 6.3 ± 1.3 μM. Atropine (1 μM), the NMDAR antagonist d,l-2-amino-5-phosphonopentanoic acid (D,L-AP5, 50 μM), and the α7 nAChR antagonist methyllycaconitine (MLA, 10 nM) did not prevent THP-induced inhibition of synaptic transmission. THP (10 μM) did not affect the probability of transmitter release because it had no effect on the frequency of miniature IPSCs and EPSCs recorded in the presence of tetrodotoxin. Additionally, THP had no effect on the amplitudes and decay-time constants of miniature IPSCs and EPSCs; therefore, it did not affect the activity of postsynaptic GABAA and glutamate receptors. This study provides the first demonstration that THP can suppress action potential-dependent synaptic transmission via a mechanism independent of NMDAR, mAChR, and α7 nAChR inhibition.

The effect of acute topiramate administration on morphine withdrawal syndrome and brain-derived neurotrophic factor in central nervous system

ABSTRACT Objectives Nucleus accumbens plays an important role in opioid addiction. Topiramate, increases postsynaptic gamma-aminobutyric acid receptor activity and antagonizes glutamatergic activity. Brain-derived neurotrophic factor (BDNF), which plays a key role in synaptic plasticity, is produced from proBDNF. The aim of this study is to investigate the effects of 100 µM topiramate applied into the lateral ventricle or nucleus accumbens on naloxone-induced morphine withdrawal and the BDNF/proBDNF ratio in the frontal cortex. Methods In the study, 36 adult male Wistar rats weighing 250–350 g were used. Morphine dependence was created with morphine pellets following guide cannula implantations. Withdrawal findings were evaluated in naloxone-induced morphine withdrawal syndrome following topiramate administration, and locomotor activity measurements were performed simultaneously. The brains of sacrificed animals were removed for determination of BDNF/proBDNF ratio. Results Topiramate administered by either route significantly suppressed the number of jumps in morphine withdrawal. Topiramate applied into the nucleus accumbens significantly reduced stereotypical behavior in morphine withdrawal, but did not cause any changes in other locomotor activity behaviors. Topiramate applied into the lateral ventricle significantly decreased the BDNF/proBDNF ratio, whereas administered into the nucleus accumbens significantly increased this ratio. Conclusion The findings of this study indicate that topiramate administered into the lateral ventricle and nucleus accumbens reduces naloxone-induced morphine withdrawal symptoms, stereotypical locomotor activity, and changes the BDNF/proBDNF ratio.

Oxytocin excites dorsal raphe serotonin neurons and bidirectionally gates their glutamate synapses

Oxytocin (OXT) modulates wide spectrum of social and emotional behaviors via modulation of numerous neurotransmitter systems, including serotonin (5-HT). However, how OXT controls the function of dorsal raphe nucleus (DRN) 5-HT neurons remains unknown. Here, we reveal that OXT excites and alters the firing pattern of 5-HT neurons via activation of postsynaptic OXT receptors (OXTRs). In addition, OXT induces cell-type-specific depression and potentiation of DRN glutamate synapses by two retrograde lipid messengers, 2-arachidonoylglycerol (2-AG) and arachidonic acid (AA), respectively. Neuronal mapping demonstrates that OXT preferentially potentiates glutamate synapses of 5-HT neurons projecting to medial prefrontal cortex (mPFC) and depresses glutamatergic inputs to 5-HT neurons projecting to lateral habenula (LHb) and central amygdala (CeA). Thus, by engaging distinct retrograde lipid messengers, OXT exerts a target-specific gating of glutamate synapses on the DRN. As such, our data uncovers the neuronal mechanisms by which OXT modulates the function of DRN 5-HT neurons.

Molecular Noise in Synaptic Communication.

In synaptic molecular communication (MC), the activation of postsynaptic receptors by neurotransmitter (NTs) is governed by a stochastic reaction-diffusion process. This randomness of synaptic MC contributes to the randomness of the electrochemical downstream signal in the postsynaptic cell, called postsynaptic membrane potential (PSP). Since the randomness of the PSP is relevant for neural computation and learning, characterizing the statistics of the PSP is critical. However, the statistical characterization of the synaptic reaction-diffusion process is difficult because the reversible bi-molecular reaction of NTs with receptors renders the system nonlinear. Consequently, there is currently no model available which characterizes the impact of the statistics of postsynaptic receptor activation on the PSP. In this work, we propose a novel statistical model for the synaptic reaction-diffusion process in terms of the chemical master equation (CME). We further propose a novel numerical method which allows to compute the CME efficiently and we use this method to characterize the statistics of the PSP. Finally, we present results from stochastic particle-based computer simulations which validate the proposed models. We show that the biophysical parameters governing synaptic transmission shape the autocovariance of the receptor activation and, ultimately, the statistics of the PSP. Our results suggest that the processing of the synaptic signal by the postsynaptic cell effectively mitigates synaptic noise while the statistical characteristics of the synaptic signal are preserved. The results presented in this paper contribute to a better understanding of the impact of the randomness of synaptic signal transmission on neuronal information processing.

Trafficking proteins show limited differences in mobility across different postsynaptic spines

The function of the postsynaptic compartment is based on the presence and activity of postsynaptic receptors, whose dynamics are controlled by numerous scaffolding, signaling and trafficking proteins. Although the receptors and the scaffolding proteins have received substantial attention, the trafficking proteins have not been investigated extensively. Their mobility rates are unknown, and it is unclear how the postsynaptic environment affects their dynamics. To address this, we analyzed several trafficking proteins (α-synuclein, amphiphysin, calmodulin, doc2a, dynamin, and endophilin), estimating their movement rates in the dendritic shaft, as well as in morphologically distinct "mushroom" and "stubby" postsynapse types. The diffusion parameters were surprisingly similar across dendritic compartments, and a few differences between proteins became evident only in the presence of a synapse neck. We conclude that the movement of trafficking proteins is not strongly affected by the postsynaptic compartment, in stark contrast to the presynapse, which regulates strongly the movement of such proteins.

A transcriptomic study reveals beneficial effects of HsTX1[R14A] on the cognition of a mouse model of sporadic Alzheimer’s disease

AbstractBackgroundNeuroinflammation is a key pathological feature of Alzheimer’s disease (AD), which can be partly attributed to the chronic activation of microglia. The voltage‐gated potassium channel 1.3 (Kv1.3) is selectively upregulated in pro‐inflammatory microglia, making it an ideal therapeutic target to modulate microglia‐mediated neuroinflammation. A highly potent and selective Kv1.3 blocker (HsTX1[R14A]) developed in our laboratory can effectively suppress neuroinflammation. More importantly, chronic subcutaneous dosing of HsTX1[R14A] (1 mg/kg every 2 day) over 8 weeks improved cognitive function in a mouse model of sporadic AD, senescence accelerated mouse‐prone 8 (SAMP8). The current transcriptomic study is to explore the therapeutic benefits in the SAMP8 mouse brains from chronic dosing of HsTX1[R14A].MethodSubcutaneous dose of HsTX1[R14A] (1mg/kg every 2 day) or PBS was administered to 4‐month‐old SAMP8 mice for 8 weeks (n = 6 each). At the conclusion of treatment, mice were euthanized and RNA from the brains were extracted using RNeasy Lipid Tissue Mini Kit (Qiagen). RNA samples were processed using an MGI RNA Directional Library Preparation Set V2. Fastq files were processed using the Laxy tool and the NfCore/RNAseq (v3.2) pipeline. Reads were aligned to the Mus musculus GRCm38 reference using STAR aligner and quantified using Salmon producing the raw genes count matrix. Raw counts were then analyzed with Degust and functional enrichment analysis was performed using R packages.ResultFunctional enrichment analysis indicated an upregulation of genes associated with 1) synapse assembly, neuronal synaptic plasticity for biological process; 2) postsynaptic neurotransmitter receptor activity, glutamate receptor activity for molecular function; 3) presynaptic active zone, NMDA selective glutamate receptor complex for cellular component. A downregulation of genes associated with 1) oxidative phosphorylation, ATP synthesis coupled electron transport for biological process; 2) chemokine activity for molecular function; 3) mitochondrial proton transporting ATP synthase complex for cellular component have also been highlighted.ConclusionOverall, the transcriptomics data indicated beneficial effects of HsTX1[R14A] on cognition in a mouse model of sporadic AD, possibly achieved by improving synaptic function, altering cellular metabolism, and reducing inflammation. Further experiments are required to confirm the current transcriptomics study.

Computational models of neurotransmission at cerebellar synapses unveil the impact on network computation.

The neuroscientific field benefits from the conjoint evolution of experimental and computational techniques, allowing for the reconstruction and simulation of complex models of neurons and synapses. Chemical synapses are characterized by presynaptic vesicle cycling, neurotransmitter diffusion, and postsynaptic receptor activation, which eventually lead to postsynaptic currents and subsequent membrane potential changes. These mechanisms have been accurately modeled for different synapses and receptor types (AMPA, NMDA, and GABA) of the cerebellar cortical network, allowing simulation of their impact on computation. Of special relevance is short-term synaptic plasticity, which generates spatiotemporal filtering in local microcircuits and controls burst transmission and information flow through the network. Here, we present how data-driven computational models recapitulate the properties of neurotransmission at cerebellar synapses. The simulation of microcircuit models is starting to reveal how diverse synaptic mechanisms shape the spatiotemporal profiles of circuit activity and computation.

Potential Targets and Action Mechanism of Gastrodin in the Treatment of Attention-Deficit/Hyperactivity Disorder: Bioinformatics and Network Pharmacology Analysis.

Objective Gastrodin is a main medicinal component of traditional Chinese medicine (TCM) Gastrodia elata Blume (G. elata), presenting the potential for the treatment of attention-deficit/hyperactivity disorder (ADHD). However, the underlying targets and action mechanisms of the treatment have not been identified. Methods The gastrodin-related microarray dataset GSE85871 was obtained from the GEO database and analyzed by GEO2R to obtain differentially expressed genes (DEGs). Subsequently, the targets of gastrodin were supplemented by the Encyclopedia of Traditional Chinese Medicine (ETCM), PubChem, STITCH, and SwissTargetPrediction databases. ADHD-associated genes were collected from six available disease databases (i.e., TTD, DrugBank, OMIM, PharmGKB, GAD, and KEGG DISEASE). The potential targets of gastrodin during ADHD treatment were obtained by mapping gastrodin-related targets with ADHD genes, and their protein–protein interaction (PPI) relationship was constructed by the STRING database. The GO function and KEGG pathway enrichment analyses were performed using the ClueGO plug-in in the Cytoscape software and DAVID database, respectively. Finally, the binding affinity between gastrodin and important targets was verified by molecular docking. Results A total of 460 gastrodin-related DEGs were identified from GSE85871, and 124 known gastrodin targets were supplemented from 4 databases, including ETCM. A total of 440 genes were collected from the above 6 disease databases, and 267 ADHD-relevant genes were obtained after duplicate removal. Through mapping the 584 gastrodin targets to the 267 ADHD genes, 16 potential therapeutic targets were obtained, among which the important ones were DRD2, DRD4, CHRNA3, CYP1A1, TNF, IL6, and KCNJ3. The enrichment analysis results indicated that 16 potential targets were involved in 25 biological processes (e.g., dopamine (DA) transport) and 22 molecular functions (e.g., postsynaptic neurotransmitter receptor activity), which were mainly localized at excitatory synapses. The neuroactive ligand-receptor interaction, cholinergic synapse, and dopaminergic synapse might be the core pathways of gastrodin in ADHD treatment. Through molecular docking, it was preliminarily verified that gastrodin showed good binding activity to seven important targets and formed stable binding conformations. Conclusions Gastrodin might exert an anti-ADHD effect by upgrading the dopaminergic system and central cholinergic system, inhibiting the inflammatory response and GIRK channel, and exerting a synergistic effect with other drugs on ADHD. For this reason, gastrodin should be considered a multitarget drug for ADHD treatment.

Ca2+ signaling in postsynaptic neurons: Neuroplastin-65 regulates the interplay between plasma membrane Ca2+ ATPases and ionotropic glutamate receptors

Upon postsynaptic glutamate receptor activation, the cytosolic Ca2+ concentration rises and initiates signaling and plasticity in spines. The plasma membrane Ca2+ ATPase (PMCA) is a major player to limit the duration of cytosolic Ca2+ signals. It forms complexes with the glycoprotein neuroplastin (Np) isoforms Np55 and Np65 and functionally interplays with N-methyl-D-aspartate (NMDA)-type ionotropic glutamate receptors (iGluNRs). Moreover, binding of the Np65-specific extracellular domain to Ca2+-permeable GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type ionotropic glutamate receptors (iGluA1Rs) was found to be required for long-term potentiation (LTP). However, the link between PMCA and iGluRs function to regulate cytosolic Ca2+ signals remained unclear. Here, we report that Np65 coordinates PMCA and iGluRs’ functions to modulate the duration and amplitude of cytosolic Ca2+ transients in dendrites and spines of hippocampal neurons. Using live-cell Ca2+ imaging, acute pharmacological treatments, and GCaMP5G-expressing hippocampal neurons, we discovered that endogenous or Np65-promoted PMCA activity contributes to the restoration of basal Ca2+ levels and that this effect is dependent on iGluR activation. Super-resolution STED and confocal microscopy revealed that electrical stimulation increases the abundance of synaptic neuroplastin-PMCA complexes depending on iGluR activation and that low-rate overexpression of Np65 doubled PMCA levels and decreased cell surface levels of GluN2A and GluA1 in dendrites and Shank2-positive glutamatergic synapses. In neuroplastin-deficient hippocampi, we observed reduced PMCA and unchanged GluN2B levels, while GluN2A and GluA1 levels were imbalanced. Our electrophysiological data from hippocampal slices argues for an essential interplay of PMCA with GluN2A- but not with GluN2B-containing receptors upon induction of synaptic plasticity. Accordingly, we conclude that Np65 may interconnect PMCA with core players of glutamatergic neurotransmission to fine-tune the Ca2+ signal regulation in basal synaptic function and plasticity.

Induction of synapse formation by de novo neurotransmitter synthesis

A vital question in neuroscience is how neurons align their postsynaptic structures with presynaptic release sites. Although synaptic adhesion proteins are known to contribute in this process, the role of neurotransmitters remains unclear. Here we inquire whether de novo biosynthesis and vesicular release of a noncanonical transmitter can facilitate the assembly of its corresponding postsynapses. We demonstrate that, in both stem cell-derived human neurons as well as in vivo mouse neurons of purely glutamatergic identity, ectopic expression of GABA-synthesis enzymes and vesicular transporters is sufficient to both produce GABA from ambient glutamate and transmit it from presynaptic terminals. This enables efficient accumulation and consistent activation of postsynaptic GABAA receptors, and generates fully functional GABAergic synapses that operate in parallel but independently of their glutamatergic counterparts. These findings suggest that presynaptic release of a neurotransmitter itself can signal the organization of relevant postsynaptic apparatus, which could be directly modified to reprogram the synapse identity of neurons.

GABA-B receptors enhance GABA-A receptor currents by modulation of membrane trafficking in dentate gyrus granule cells

Activation of postsynaptic GABA-B receptors enhances tonic inhibition mediated by high-affinity extrasynaptic GABAA receptors in dentate gyrus granule cells (DGGCs), thalamocortical neurons, and cerebellar granule cells. We investigated the mechanism(s) of GABA current modulation by GABAB receptors in DGGCs using a combination of electrophysiological and biochemical approaches. In acute hippocampal brain slices the GABAB receptor agonist baclofen increased GABA-evoked currents in ∼2/3rds of DGGCs, significantly increasing GABAA currents by 41% on average. Nonstationary noise analysis was performed to estimate the effects of baclofen on single channel conductance, mean open time, and channel number; these estimates suggest that GABAB receptor activation increases receptor number but does not modify single channel properties of GABAA receptors. To directly assess baclofen-induced changes in plasma membrane expression of GABAA receptors, biotinylated western blots were performed. Treatment of hippocampal slices with baclofen significantly increased the surface expression of GABAA receptor subunits (both δ and γ2 subunits) and this effect was inhibited by the GABAB receptor antagonist CGP55845. These data indicate that changes in membrane trafficking and increased number of GABAA receptors in plasma membrane contribute to the enhancement of GABA currents produced by GABAB receptor activation in DGGCs.

Systematic analysis of the pharmacological function of Schisandra as a potential exercise supplement.

[Purpose] Exercise can prevent conditions such as atrophy and degenerative brain diseases. However, owing to individual differences in athletic ability, exercise supplements can be used to improve a person’s exercise capacity. Schisandra chinensis (SC) is a natural product with various physiologically active effects. In this study, we analyzed SC using a pharmacological network and determined whether it could be used as an exercise supplement.[Methods] The active compounds of SC and target genes were identified using the Traditional Chinese Medicine Database and Analysis Platform (TCMSP). The active compound and target genes were selected based on pharmacokinetic (PK) conditions (oral bioavailability (OB) ≥ 30%, Caco-2 permeability (Caco-2) ≥ -0.4, and drug-likeness (DL) ≥ 0.18). Gene ontology (GO) was analyzed using the Cytoscape software.[Results] Eight active compounds were identified according to the PK conditions. Twenty-one target genes were identified after excluding duplicates in the eight active compounds. The top 10 GOs were analyzed using GO-biological process analysis. GO was subsequently divided into three representative categories: postsynaptic neurotransmitter receptor activity (53.85%), an intracellular steroid hormone receptor signaling pathway (36.46%), and endopeptidase activity (10%). SC is related to immune function.[Conclusion] According to the GO analysis, SC plays a role in immunity and inflammation, promotes liver metabolism, improves fatigue, and regulates the function of steroid receptors. Therefore, we suggest SC as an exercise supplement with nutritional and anti-fatigue benefits.

New Serotonin-Norepinephrine Reuptake Inhibitors and Their Anesthetic and Analgesic Considerations.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit the presynaptic neuronal uptake of serotonin and norepinephrine and prolong the effects of the monoamines in the synaptic cleft within the central nervous system, leading to increased postsynaptic receptor activation and neuronal activities. Serotonin-norepinephrine reuptake inhibitors can have multiple clinical indications, including as the first-line agents for the management of depression and anxiety, and as analgesics in the treatment of chronic pain. The effects of reuptake inhibition of norepinephrine and serotonin are often dose-dependent and agent-dependent. There are five FDA-approved serotonin-norepinephrine reuptake inhibitors (desvenlafaxine, duloxetine, levomilnacipran, milnacipran and sibutramine) currently being marketed in the United States. As the COVID-19 pandemic significantly increased the incidence and prevalence of anxiety and depression across the country, there are significantly increased prescriptions of these medications perioperatively. Thus, anesthesiologists are more likely than ever to have patients administered with these agents and scheduled for elective or emergency surgical procedures. A thorough understanding of these commonly prescribed serotonin-norepinephrine reuptake inhibitors and their interactions with commonly utilized anesthetic agents is paramount. There are two potentially increased risks related to the continuation of SNRIs through the perioperative period: intraoperative bleeding and serotonin syndrome. SNRIs have some off-label uses, more new indications, and ever-increasing new applications in perioperative practice. This article aims to review the commonly prescribed serotonin-norepinephrine reuptake inhibitors and the current clinical evidence regarding their considerations in perioperative anesthesia and analgesia.

Sustained postsynaptic kainate receptor activation downregulates AMPA receptor surface expression and induces hippocampal LTD

SummaryIt is well established that long-term depression (LTD) can be initiated by either NMDA or mGluR activation. Here we report that sustained activation of GluK2 subunit-containing kainate receptors (KARs) leads to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis and induces LTD of AMPARs (KAR-LTDAMPAR) in hippocampal neurons. The KAR-evoked loss of surface AMPARs is blocked by the ionotropic KAR inhibitor UBP 310 indicating that KAR-LTDAMPAR requires KAR channel activity. Interestingly, however, blockade of PKC or PKA also reduces GluA2 surface expression and occludes the effect of KAR activation. In acute hippocampal slices, kainate application caused a significant loss of GluA2-containing AMPARs from synapses and long-lasting depression of AMPAR excitatory postsynaptic currents in CA1. These data, together with our previously reported KAR-LTPAMPAR, demonstrate that KARs can bidirectionally regulate synaptic AMPARs and synaptic plasticity via different signaling pathways.

Subsynaptic positioning of AMPARs by LRRTM2 controls synaptic strength.

Recent evidence suggests that nano-organization of proteins within synapses may control the strength of communication between neurons in the brain. The unique subsynaptic distribution of glutamate receptors, which cluster in nanoalignment with presynaptic sites of glutamate release, supports this hypothesis. However, testing it has been difficult because mechanisms controlling subsynaptic organization remain unknown. Reasoning that transcellular interactions could position AMPA receptors (AMPARs), we targeted a key transsynaptic adhesion molecule implicated in controlling AMPAR number, LRRTM2, using engineered, rapid proteolysis. Severing the LRRTM2 extracellular domain led quickly to nanoscale declustering of AMPARs away from release sites, not prompting their escape from synapses until much later. This rapid remodeling of AMPAR position produced significant deficits in evoked, but not spontaneous, postsynaptic receptor activation. These results dissociate receptor numbers from their nanopositioning in determination of synaptic function and support the novel concept that adhesion molecules acutely position receptors to dynamically control synaptic strength.

Muscarinic regulation of the neuronal Na+/K+‐ATPase in rat hippocampus

Stimulation of postsynaptic muscarinic receptors was shown to excite principal hippocampal neurons by modulating several membrane ion conductances. We show here that activation of postsynaptic muscarinic receptors also causes neuronal excitation by inhibiting Na+ /K+ -ATPase activity. Muscarinic Na+ /K+ -ATPase inhibition is mediated by two separate signalling pathways that lead downstream to enhanced Na+ /K+ -ATPase phosphorylation by activating protein kinase C and protein kinase G. Muscarinic excitation through Na+ /K+ -ATPase inhibition is probably involved in cholinergic modulation of hippocampal activity and may turn out to be a widespread mechanism of neuronal excitation in the brain. Stimulation of muscarinic cholinergic receptors on principal hippocampal neurons enhances intrinsic neuronal excitability by modulating several membrane ion conductances. The electrogenic Na+ /K+ -ATPase (NKA; the 'Na+ pump') is a ubiquitous regulator of intrinsic neuronal excitability, generating a hyperpolarizing current to thwart excessive neuronal firing. Using electrophysiological and pharmacological methodologies in rat hippocampal slices, we show that neuronal NKA pumping activity is also subjected to cholinergic regulation. Stimulation of postsynaptic muscarinic, but not nicotinic, cholinergic receptors activates membrane-bound phospholipase C and hydrolysis of membrane-integral phosphatidylinositol 4,5-bisphosphate into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3 ). Along one signalling pathway, DAG activates protein kinase C (PKC). Along a second signalling pathway, IP3 causes Ca2+ release from the endoplasmic reticulum, facilitating nitric oxide (NO) production. The rise in NO levels stimulates cGMP synthesis by guanylate-cyclase, activating protein kinase G (PKG). The two pathways converge to cause partial NKA inhibition through enzyme phosphorylation by PKC and PKG, leading to a marked increase in intrinsic neuronal excitability. This novel mechanism of neuronal NKA regulation probably contributes to the cholinergic modulation of hippocampal activity in spatial navigation, learning and memory.