Regulation Of Synaptic Plasticity Research Articles

Research progress of acupuncture regulating ERK signaling pathway in the treatment of depression.

Acupuncture treatment for depression has definite therapeutic efficacy, and its mechanism has been extensively studied. The extracellular regulatory protein kinase(ERK) signaling pathway is involved in the development and progression of depression. This article reviewed and summarized the research progress on the regulation of the ERK signaling pathway by acupuncture in the treatment of depression in recent years, focusing on the physiological activation and regulatory mechanism of the ERK signaling pathway, its association with the occurrence of depression, and the mechanisms through which acupuncture activates the ERK signaling pathway to treat depression (including enhancing neuronal synaptic plasticity, promoting the release of neurotrophic factors, and inhibiting neuronal apoptosis). Future research could explore the relationship between the ERK pathway and other pathways, investigate other brain regions besides the prefrontal cortex and hippocampus, examine differences in regulatory mechanisms between male and female patients, assess the effects of different acupuncture techniques on the ERK pathway, and increase efforts to explore mechanism of synaptic plasticity regulation, so as to provide reference for the clinical application and mechanism sludy of acupuncture in depression treatment.

Environmental enrichment and the combined interventions of EE and metformin enhance hippocampal neuron survival and hippocampal-dependent memory in type 2 diabetic rats under stress through the BDNF-TrkB signaling pathways

BackgroundType 2 diabetes (T2D) with depression causes severe cognitive impairments. The devastating conditions will further compromise the overall quality of life. The overconsumption of high-fat and high-sucrose (HFS) diet is one of the modifiable risk factors for T2D, depression, and cognitive impairments. Thus, it is essential to identify effective therapeutic strategies to overcome the cognitive impairments in T2D with depression. We proposed environmental enrichment (EE) which encompasses social, cognitive, and physical components as the alternative treatment for such impairments. We also investigated the potential neuroprotective properties of the antidiabetic drug metformin. This study aimed to investigate the effects of EE and metformin interventions on hippocampal neuronal death, and hippocampal-dependent memory impairment in T2D rats under stress. MethodsThirty-two male rats (200–250 g) were divided into four groups: C group (standard diet + conventional cage), DS group [HFS-induced T2D + restraint stress (RS)], DSE group [HFS-induced T2D + RS + EE] and DSEM group [HFS + RS + EE + metformin]. Serum corticosterone (CORT) was measured to evaluate stress levels. The serum Free Oxygen Radicals Testing (FORT) and Free Oxygen Radicals Defence Test (FORD) were measured to evaluate the systemic oxidative status (OS). Serum brain-derived neurotrophic factor (BDNF) and T-maze tasks were performed to evaluate cognitive functions. Rats were humanely sacrificed to collect brains for histological, morphometric, and hippocampal gene expression studies. ResultsThe CORT and the serum FORT levels in the DSE and DSEM groups were lower than in the DS group. Meanwhile, the serum BDNF, T-maze scores, histological, and morphometric analysis were improved in the DSE and DSEM groups than in the DS group. These findings supported that EE and the combined interventions of EE and metformin had neuroprotective properties. The hippocampal gene expression analysis revealed that the DSE and DSEM groups showed improved regulation of BDNF-TrkB signalling pathways, including the BDNF/TrkB binding, PI3K – Akt pathway, Ras–MAPK pathway, PLCγ–Ca2+ pathway, and CREB transcription. ConclusionEE and the combined interventions of EE and metformin improved hippocampal neuron survival and hippocampal-dependent memory in T2D rats under stress by enhancing gene expression regulation of neurogenesis and synaptic plasticity.

MiRNAs in treatment-resistant depression: a systematic review.

Treatment-resistant depression (TRD) is a condition in a subset of depressed patients characterized by resistance to antidepressant medications. The global prevalence of TRD has been steadily increasing, yet significant advancements in its diagnosis and treatment remain elusive despite extensive research efforts. The precise underlying pathogenic mechanisms are still not fully understood. Epigenetic mechanisms play a vital role in a wide range of diseases. In recent years, investigators have increasingly focused on the regulatory roles of miRNAs in the onset and progression of TRD. miRNAs are a class of noncoding RNA molecules that regulate the translation and degradation of their target mRNAs via interaction, making the exploration of their functions in TRD essential for elucidating their pathogenic mechanisms. A systematic search was conducted in four databases, namely PubMed, Web of Science, Cochrane Library, and Embase, focusing on studies related to treatment-resistant depression and miRNAs. The search was performed using terms individually or in combination, such as "treatment-resistant depression," "medication-resistant depression," and "miRNAs." The selected articles were reviewed and collated, covering the time period from the inception of each database to the end of February 2024. We found that miRNAs play a crucial role in the pathophysiology of TRD through three main aspects: 1) involvement in miRNA-mediated inflammatory responses (including miR-155, miR-345-5p, miR-146a, and miR-146a-5p); 2) influence on 5-HT transport processes (including miR-674,miR-708, and miR-133a); and 3) regulation of synaptic plasticity (including has-miR-335-5p,has-miR- 1292-3p, let-7b, and let-7c). Investigating the differential expression and interactions of these miRNAs could contribute to a deeper understanding of the molecular mechanisms underlying TRD. miRNAs might play a pivotal role in the pathogenesis of TRD. Gaining a deeper understanding of the roles and interrelations of miRNAs in TRD will contribute to elucidating disease pathogenesis and potentially provide avenues for the development of novel diagnostic and therapeutic strategies.

Hippocampal proteome comparison of infant and adult Fmr1 deficiency mice reveals adult-related changes associated with postsynaptic density

Deficiency in fragile X mental retardation 1 (Fmr1) leads to loss of its encoded protein FMRP and causes fragile X syndrome (FXS) by dysregulating its target gene expression in an age-related fashion. Using comparative proteomic analysis, this study identified 105 differentially expressed proteins (DEPs) in the hippocampus of postnatal day 7 (P7) Fmr1−/y mice and 306 DEPs of P90 Fmr1−/y mice. We found that most DEPs in P90 hippocampus were not changed in P7 hippocampus upon FMRP absence, and some P90 DEPs exhibited diverse proteophenotypes with abnormal expression of protein isoform or allele variants. Bioinformatic analyses showed that the P7 DEPs were mainly enriched in fatty acid metabolism and oxidoreductase activity and nutrient responses; whereas the P90 PEPs (especially down-regulated DEPs) were primarily enriched in postsynaptic density (PSD), neuronal projection development and synaptic plasticity. Interestingly, 25 of 30 down-regulated PSD proteins present in the most enriched protein to protein interaction network, and 6 of them (ANK3, ATP2B2, DST, GRIN1, SHANK2 and SYNGAP1) are both FMRP targets and autism candidates. Therefore, this study suggests age-dependent alterations in hippocampal proteomes upon loss of FMRP that may be associated with the pathogenesis of FXS and its related disorders. SignificanceIt is well known that loss of FMRP resulted from Fmr1 deficiency leads to fragile X syndrome (FXS), a common neurodevelopmental disorder accompanied by intellectual disability and autism spectrum disorder (ASD). FMRP exhibits distinctly spatiotemporal patterns in the hippocampus between early development and adulthood, which lead to distinct dysregulations of gene expression upon loss of FMRP at the two age stages potentially linked to age-related phenotypes. Therefore, comparison of hippocampal proteomes between infancy and adulthood is valuable to provide insights into the early causations and adult-dependent consequences for FXS and ASD. Using a comparative proteomic analysis, this study identified 105 and 306 differentially expressed proteins (DEPs) in the hippocampi of postnatal day 7 (P7) and P90 Fmr1−/y mice, respectively. Few overlapping DEPs were identified between P7 and P90 stages, and the P7 DEPs were mainly enriched in the regulation of fatty acid metabolism and oxidoreduction, whereas the P90 DEPs were preferentially enriched in the regulation of synaptic formation and plasticity. Particularly, the up-regulated P90 proteins are primarily involved in immune responses and neurodegeneration, and the down-regulated P90 proteins are associated with postsynaptic density, neuron projection and synaptic plasticity. Our findings suggest that distinctly changed proteins in FMRP-absence hippocampus between infancy and adulthood may contribute to age-dependent pathogenesis of FXS and ASD.

The SNX17-Retriever endosomal recycling pathway is a key regulator of synaptic function and plasticity in hippocampal neurons

The insertion and removal of integral membrane proteins is a key mechanism for the regulation of synaptic function. Once surface proteins are internalized, they can either be routed to lysosomes for degradation or can be recycled back to the cell surface. Two recycling protein complexes - the SNX27-Retromer complex and the recently discovered SNX17-Retriever complex - are the main drivers in recycling internalized cargoes in non-neuronal cells. In neurons, the SNX27-Retromer pathway has been shown to regulate surface expression of AMPA-type glutamate receptors (AMPARs) during long-term potentiation (LTP), but almost nothing is known regarding the role of the SNX17-Retriever pathway at synapses. Here, using cultured hippocampal neurons, we demonstrate that the SNX17-Retriever pathway localizes to both synaptic and extra-synaptic sites and that RNAi-mediated disruption of this pathway leads to the functional and structural loss of excitatory synapses. Moreover, we find that synaptic stimulation leads to the recruitment of SNX17 to synaptic sites in a manner that depends on Ca2+ influx through NMDARs, activation of CaMKII, and Retriever complex binding. Knockdown of either SNX17 or the Retriever subunit DSCR3 prevents structural plasticity of dendritic spines during LTP. Finally, this loss of structural plasticity is associated with altered traffcking of the cell adhesion molecule β1 Integrin, which is a SNX17 cargo in non-neuronal cells and as we show, in neurons as well. Additionally, SNX17-Retriever is shown to not play a role in AMPAR recycling. Preliminary studies suggest that SNX27 and SNX17 sort distinct cargos in neurons, suggesting that these two recycling pathways each play important, but unique, roles at synaptic sites. National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under award numbers R01-NS129198 to L.S. Weisman and M.A. Sutton, R01-NS099340 and R01- NS064015 to L.S. Weisman, R01-NS097498 to M.A. Sutton, and R21-NS125449, and R01-NS116008 to S. Iwase, by the National Institute of Mental Health (NIMH) of the NIH under award number R21-MH127485 to S. Iwase. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Structural characterization of two nanobodies targeting the ligand-binding pocket of human Arc.

The activity-regulated cytoskeleton-associated protein (Arc) is a complex regulator of synaptic plasticity in glutamatergic neurons. Understanding its molecular function is key to elucidate the neurobiology of memory and learning, stress regulation, and multiple neurological and psychiatric diseases. The recent development of anti-Arc nanobodies has promoted the characterization of the molecular structure and function of Arc. This study aimed to validate two anti-Arc nanobodies, E5 and H11, as selective modulators of the human Arc N-lobe (Arc-NL), a domain that mediates several molecular functions of Arc through its peptide ligand binding site. The structural characteristics of recombinant Arc-NL-nanobody complexes were solved at atomic resolution using X-ray crystallography. Both anti-Arc nanobodies bind specifically to the multi-peptide binding site of Arc-NL. Isothermal titration calorimetry showed that the Arc-NL-nanobody interactions occur at nanomolar affinity, and that the nanobodies can displace a TARPγ2-derived peptide from the binding site. Thus, both anti-Arc-NL nanobodies could be used as competitive inhibitors of endogenous Arc ligands. Differences in the CDR3 loops between the two nanobodies indicate that the spectrum of short linear motifs recognized by the Arc-NL should be expanded. We provide a robust biochemical background to support the use of anti-Arc nanobodies in attempts to target Arc-dependent synaptic plasticity. Function-blocking anti-Arc nanobodies could eventually help unravel the complex neurobiology of synaptic plasticity and allow to develop diagnostic and treatment tools.

The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.

Acteoside Attenuates Recognition Memory Impairment in CUMS Rats via Regulating Synaptic Plasticity and mTOR Signaling Pathway

Acteoside Attenuates Recognition Memory Impairment in CUMS Rats via Regulating Synaptic Plasticity and mTOR Signaling Pathway

Relationship between brain-derived neurotrophic factor and mild to moderate cognitive impairment in the older Mexican population

BackgroundMild–moderate cognitive impairment is a frequent pathology in the adult population. It is important to explore early expression biomarkers that contribute to early detection and benefit the prognostic outlook. Brain-derived neurotrophic factor (BDNF) is an essential regulator of synaptic plasticity, neuronal survival, and differentiation, and even a critical molecular target for drug development in neurological disorders. It is crucial to carry out studies in the early stages that better clarify the landscape of BDNF. ObjectiveTo compare the serum levels of BDNF in healthy adult patients and those with mild to moderate cognitive impairment. Materials and methodsA casecontrol study in patients over 55- years with cognitive impairment, obtained by the MMSE® and MoCA® screening scales. A total of 191 patients, 102 patients with cognitive impairment (cases) and 89 healthy ones (controls) participated in the study. Blood samples were collected to obtain serum, with the determination of BDNF concentrations. For differences in BDNF concentrations, a one-way analysis of variance was used. The significance level of p<.05. ResultsThe mean serum concentration of BDNF in the case group was 277.68±75.09 vs. the control group, where the concentration was 354.97±66.06 pg/ml (p=.001). ConclusionsThere is an association between decreased BDNF levels and mild and moderate cognitive impairment in our study population.

Long non‐coding RNA CASC15 enhances learning and memory in mice by promoting synaptic plasticity in hippocampal neurons

AbstractAlzheimer's disease (AD) is a debilitating systemic disorder that has a detrimental impact on the overall well‐being of individuals. Emerging research suggests that long non‐coding RNAs play a role in neural development and function. Nevertheless, the precise relationship between lncRNAs and Alzheimer's disease remains uncertain. The authors' recent discoveries have uncovered an unconventional mechanism involving the regulation of synaptic plasticity and the functioning of the hippocampal fragile X mental retardation protein 1 (FMR1)—neurotrophin 3 (NTF3) pathway, which is mediated by cancer susceptibility candidate 15 (CASC15). Subsequently, functional rescue experiments were performed to illustrate the efficient delivery of exosomes harboring a significant amount of 2610307p16Rik transcripts, which is the murine equivalent of human CASC15, to the hippocampal region of mice. This resulted in significant improvements in synaptic morphological plasticity and cognitive function in APP/PS1 mice. Given the pivotal involvement of CASC15 in synaptic plasticity and the distinctive regulatory mechanisms of the CASC15‐FMR1‐NTF3 axis, CASC15 emerges as a promising biomarker for Alzheimer's disease and may even possess potential as a feasible therapeutic target.

Tanshinone IIA Regulates Synaptic Plasticity in Mg2+-Free-Induced Epileptic Hippocampal Neurons via the PI3K/Akt Signaling Pathway.

Tanshinone IIA (TSIIA) is an element of the effective ingredients of Salvia miltiorrhiza Bunge (Labiatae), exhibits a significant therapeutic effect in brain neuroprotection. The focus of this study was the examination of synaptic plasticity of in Mg2+-free-induced epileptic hippocampus neurons and how TSIIA protects against it. The purity of the primary hippocampal neurons extracted from Sprague Dawley rats was assessed within 24 hours by microtubule-associated protein (MAP2) immunofluorescence staining. A hippocampal neuron model for Mg2+-free-induced spontaneous recurrent epileptiform discharge was developed, five experimental groups were then randomized: blank (Blank), model (Model), TSIIA (TSIIA, 20 µM), LY294002 (LY294002, 25 µM), and TSIIA+LY294002 (TSIIA+LY294002, 20 µM+25 µM). FIJI software was used to examine variations of neurite complexity, total length of hippocampal neurons, number of primary dendrites and density of dendritic spines. Developmental regulation brain protein (Drebrin) and brain-derived neurotrophic factor (BDNF) expression was evaluated using immunofluorescence staining and the relative expression of phospho-protein kinase B (p-Akt)/Akt, BDNF, synaptophysin (SYN) and postsynaptic density 95 (PSD-95) determined by Western blot. In contrast to the model group, TSIIA drastically reduced damage to synaptic plasticity of hippocampal neurons caused by epilepsy (p < 0.05). The TSIIA group showed a significant increase in the relative expression of PSD-95, SYN, BDNF, and p-Akt/Akt (p < 0.01). TSIIA was effective in reducing harm to the synaptic plasticity of hippocampal neurons induced by persistent status epilepticus, with the possible mechanism being regulation of the phosphatidylinositol 3-kinase 56 (PI3K)/Akt signaling pathway.

Microglia-neuron interactions in schizophrenia.

Multiple lines of evidence implicate increased neuroinflammation mediated by glial cells to play a key role in neurodevelopmental disorders such as schizophrenia. Microglia, which are the primary innate immune cells of the brain, are crucial for the refinement of the synaptic circuitry during early brain development by synaptic pruning and the regulation of synaptic plasticity during adulthood. Schizophrenia risk factors as genetics or environmental influences may further be linked to increased activation of microglia, an increase of pro-inflammatory cytokine levels and activation of the inflammasome resulting in an overall elevated neuroinflammatory state in patients. Synaptic loss, one of the central pathological hallmarks of schizophrenia, is believed to be due to excess removal of synapses by activated microglia, primarily affecting glutamatergic neurons. Therefore, it is crucial to investigate microglia-neuron interactions, which has been done by multiple studies focusing on post-mortem brain tissues, brain imaging, animal models and patient iPSC-derived 2D culture systems. In this review, we summarize the major findings in patients and in vivo and in vitro models in the context of neuron-microglia interactions in schizophrenia and secondly discuss the potential of anti-inflammatory treatments for the alleviation of positive, negative, and cognitive symptoms.

Erratum: Liu et al., "TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury".

Erratum: Liu et al., "TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury".

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.

Lactobacillus plantarum LLY-606 Supplementation Ameliorates the Cognitive Impairment of Natural Aging in Mice: The Potential Role of Gut Microbiota Homeostasis.

This work explored the effects of Lactobacillus plantarum LLY-606 (LLY-606) on cognitive function in aging mice. Our findings demonstrated that LLY-606 effectively prolonged the lifespan of mice and improved age-related cognitive impairments. Additionally, our study revealed that supplementation with LLY-606 resulted in the downregulation of inflammatory cytokine levels and the upregulation of antioxidant capacity. Furthermore, probiotic supplementation effectively mitigated the deterioration of the intestinal barrier function in aging mice. Amplicon analysis indicated the successful colonization of probiotics, facilitating the regulation of age-induced gut microbiota dysbiosis. Notably, the functional abundance prediction of microbiota indicated that tryptophan metabolism pathways, glutamatergic synapse pathways, propanoate metabolism pathways, and arginine and proline metabolism pathways were enriched after the LLY-606 intervention. In summary, LLY-606 emerged as a potential functional probiotic capable of influencing cognitive function in aging mice. This effect was achieved through the modulation of gut microbiota, the regulation of synaptic plasticity, and the enhancement of neurotrophic factor levels.

A cytoskeleton symphony: Actin and microtubules in microglia dynamics and aging

Microglia dynamically reorganize their cytoskeleton to perform essential functions such as phagocytosis of toxic protein aggregates, surveillance of the brain parenchyma, and regulation of synaptic plasticity during neuronal activity bursts. Recent studies have shed light on the critical role of the microtubule cytoskeleton in microglial reactivity and function, revealing key regulators like cyclin-dependent kinase 1 and centrosomal nucleation in the remodeling of microtubules in activated microglia. Concurrently, the role of the actin cytoskeleton is also pivotal, particularly in the context of small GTPases like RhoA, Rac1, and Cdc42 and actin-binding molecules such as profilin-1 and cofilin. This article delves into the intricate molecular landscape of actin and microtubules, exploring their synergistic roles in driving microglial cytoskeletal dynamics. We propose a more integrated view of actin and microtubule cooperation, which is fundamental to understanding the functional coherence of the microglial cytoskeleton and its pivotal role in propelling brain homeostasis. Furthermore, we discuss how alterations in microglial cytoskeleton dynamics during aging and in disease states could have far-reaching implications for brain function. By unraveling the complexities of microglia cytoskeletal dynamics, we can deepen our understanding of microglial functional states and their implications in health and disease, offering insights into potential therapeutic interventions for neurologic disorders.

IKKβ deletion from CNS macrophages increases neuronal excitability and accelerates the onset of EAE, while from peripheral macrophages reduces disease severity

BackgroundMultiple sclerosis (MS) is a neuroinflammatory demyelinating disease characterized by motor deficits and cognitive decline. Many immune aspects of the disease are understood through studies in the experimental autoimmune encephalomyelitis (EAE) model, including the contribution of the NF-κB transcription factor to neuroinflammation. However, the cell-specific roles of NF-κB to EAE and its cognitive comorbidities still needs further investigation. We have previously shown that the myeloid cell NF-κB plays a role in the healthy brain by exerting homeostatic regulation of neuronal excitability and synaptic plasticity and here we investigated its role in EAE.MethodsWe used constitutive MφIKKβΚΟ mice, in which depletion of IKKβ, the main activating kinase of NF-κB, was global to CNS and peripheral macrophages, and ΜgΙΚΚβKO mice, in which depletion was inducible and specific to CNS macrophages by 28 days after tamoxifen administration. We subjected these mice to MOG35-55 induced EAE and cuprizone-induced demyelination. We measured pathology by immunohistochemistry, investigated molecular mechanisms by RNA sequencing analysis and studied neuronal functions by in vivo electrophysiology in awake animals.ResultsGlobal depletion of IKKβ from myeloid cells in MφIKKβΚΟ mice accelerated the onset and significantly supressed chronic EAE. Knocking out IKKβ only from CNS resident macrophages accelerated the onset and exacerbated chronic EAE, accompanied by earlier demyelination and immune cell infiltration but had no effect in cuprizone-induced demyelination. Peripheral T cell effector functions were not affected by myeloid cell deletion of IKKβ, but CNS resident mechanisms, such as microglial activation and neuronal hyperexcitability were altered from early in EAE. Lastly, depletion of myeloid cell IKKβ resulted in enhanced late long-term potentiation in EAE.ConclusionsIKKβ-mediated activation of NF-κΒ in myeloid cells has opposing roles in EAE depending on the cell type and the disease stage. In CNS macrophages it is protective while in peripheral macrophages it is disease-promoting and acts mainly during chronic disease. Although clinically protective, CNS myeloid cell IKKβ deletion dysregulates neuronal excitability and synaptic plasticity in EAE. These effects of IKKβ on brain cognitive abilities deserve special consideration when therapeutic interventions that inhibit NF-κB are used in MS.

The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation.

Chronic pain is sustained, in part, through the intricate process of central sensitization (CS), marked by maladaptive neuroplasticity and neuronal hyperexcitability within central pain pathways. Accumulating evidence suggests that CS is also driven by neuroinflammation in the peripheral and central nervous system. In any chronic disease, the search for perpetuating factors is crucial in identifying therapeutic targets and developing primary preventive strategies. The brain-derived neurotrophic factor (BDNF) emerges as a critical regulator of synaptic plasticity, serving as both a neurotransmitter and neuromodulator. Mounting evidence supports BDNF's pro-nociceptive role, spanning from its pain-sensitizing capacity across multiple levels of nociceptive pathways to its intricate involvement in CS and neuroinflammation. Moreover, consistently elevated BDNF levels are observed in various chronic pain disorders. To comprehensively understand the profound impact of BDNF in chronic pain, we delve into its key characteristics, focusing on its role in underlying molecular mechanisms contributing to chronic pain. Additionally, we also explore the potential utility of BDNF as an objective biomarker for chronic pain. This discussion encompasses emerging therapeutic approaches aimed at modulating BDNF expression, offering insights into addressing the intricate complexities of chronic pain.

Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum.

Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting habitual learning. The aim of this study was to outline the role of astrocytes in regulating eCB signaling in the DLS. To this end, we employed electrophysiological slice recordings combined with metabolic, chemogenetic and pharmacological approaches in an attempt to selectively suppress astrocyte function. High-frequency stimulation induced eCB-mediated LTD (HFS-LTD) in brain slices from both male and female rats. The metabolic uncoupler fluorocitrate (FC) reduced the probability of transmitter release and depressed synaptic output in a manner that was independent on cannabinoid 1 receptor (CB1R) activation. Fluorocitrate did not affect the LTD induced by the CB1R agonist WIN55,212-2, but enhanced CB1R-dependent HFS-LTD. Reduced neurotransmission and facilitated HFS-LTD were also observed during chemogenetic manipulation using Gi-coupled DREADDs targeting glial fibrillary acidic protein (GFAP)-expressing cells, during the pharmacological inhibition of connexins using carbenoxolone disodium, or during astrocytic glutamate uptake using TFB-TBOA. While pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) failed to prevent synaptic depression induced by FC, it blocked the facilitation of HFS-LTD. While the lack of tools to disentangle astrocytes from neurons is a major limitation of this study, our data collectively support a role for astrocytes in modulating basal neurotransmission and eCB-mediated synaptic plasticity.

Https://fz.kiev.ua/index.php?abs=2034

Investigation of the mechanism of neuronal communication underlies the fundamental discoveries that promote health. The studies of oxytocin signaling in neurons from or within different brain areas are directed to explore the role of this neurohormonal modulator in the regulation of synaptic transmission and plasticity, neuronal excitability that contributes to the reproduction, social behavior and learning capacity, anxiety, inflammation and differentiation in the brain. Oxytocin is synthesized in supraoptic and paraventricular nuclei of the hypothalamus and when secreted into the bloodstream from the posterior pituitary, it produces a significant effect on uterine contraction and lactation. At the same time this nonapeptide being released within the limbic system and brain cortex modulates neuronal activity by affecting ion channels on their membranes. The oxytocin receptor is primarily coupled to Gq/11 proteins causing phospholipase C activation, Ca2+ release and store-operated Ca2+ entry. These pathways are central for the regulation of the activity of different types of TRP channels, especially of the canonical subfamily (TRPC). Here we highlight the link between oxytocin signaling, which is particularly well investigated in the myometrium, and receptor-operated TRPC4 and multimodal TRPV4 ion channels that participate in oxytocin-dependent regulation of the uterine smooth muscle contractility under various conditions. Importantly, similarly to oxytocin, these channels have been implicated in neuropathic pain behavior, anxiety, fear and depression. Since similar signal transduction pathways are likely to be functional in neuronal cells, we propose that future studies of oxytocin effects in the CNS should also consider the role of these Ca2+-permeable channels.