Receptor Function Research Articles

Role of neurogenic inflammation in intervertebral disc degeneration

In healthy intervertebral discs (IVDs), nerves and blood vessels are present only in the outer annulus fibrosus, while in degenerative IVDs, a large amount of nerve and blood vessel tissue grows inward. Evidence supports that neurogenic inflammation produced by neuropeptides such as substance P and calcitonin gene related peptide released by the nociceptive nerve fibers innervating the IVDs plays a crucial role in the process of IVD degeneration. Recently, non-neuronal cells, including IVD cells and infiltrating immune cells, have emerged as important players in neurogenic inflammation. IVD cells and infiltrating immune cells express functional receptors for neuropeptides through which they receive signals from the nervous system. In return, IVD cells and immune cells produce neuropeptides and nerve growth factor, which stimulate nerve fibers. This communication generates a positive bidirectional feedback loop that can enhance the inflammatory response of the IVD. Recently emerging transient receptor potential channels have been recognized as contributors to neurogenic inflammation in the degenerative IVDs. These findings suggest that neurogenic inflammation involves complex pathophysiological interactions between sensory nerves and multiple cell types in the degenerative IVDs. Clarifying the mechanism of neurogenic inflammation in IVD degeneration may provide in-depth understanding of the pathology of discogenic low back pain.

Evidence for Bxy-npr-21 on controlling juveniles' growth and modulating male sexual arousal: from molecules to behaviors.

Bursaphelenchus xylophilus is considered a quarantine plant nematode species, that causes major damage to pine ecosystems globally. However, there are few reports on the identification and function of the sex pheromone receptors involved in mating. The function of Bxy-npr-21 as a potential sex pheromone receptor gene was verified from molecules to behaviors in this study. Here, we firstly report that Bxy-npr-21 is a receptor gene involved in sexual attraction. The bioinformatic analysis indicated that the Bxy-npr-21 gene in B. xylophilus encodes a GPCR. The expression characterization for Bxy-npr-21 showed that it is widely expressed in whole body of larvae and sex organs of adults. The RNAi results suggested that the Bxy-npr-21 gene was involved mainly in movement, feeding, and mating. Sexual arousal experiments further validated that the Bxy-npr-21 gene was involved in the activation of males by female chemical signaling. Our results strongly suggest that the Bxy-npr-21 gene is a key gene that regulates nematode growth, development and reproduction. The results of this study lay the foundation for revealing the molecular mechanisms of growth and reproduction of B. xylophilus. It can also provide an important basis for further control of B. xylophilus. © 2025 Society of Chemical Industry.

Function of formyl peptide receptor 2 in adriamycin resistance of breast cancer

FPRL2 has been shown to be associated with a variety of tumours but has not been well studied in breast cancer. In this study, We combine molecular biology techniques with bioinformatics to analyze the role of FPRL2 in breast cancer and adriamycin resistance. By utilizing bioinformatics, we mine TCGA and GEO public databases to assess FPRL2 expression in breast cancer patients and its correlation with patient prognosis. Additionally, we employ the DepMap tool to probe the CCLE database, examining the relationship between FPRL2 gene effects and adriamycin sensitivity. Chemosensitivity of Adriamycin in breast cancer cells was tested by CCK-8 method. The apoptosis of breast cancer cells was determined by flow cytometry assay. Expression of p-ERK5 and p-AKT was determined by Western blot assay. Our results indicate that the expression level of FPRL2 in tumor tissues of breast cancer patients is significantly higher than that in normal tissues, and it correlates with poor prognosis in patients. Furthermore, the expression level of FPRL2 in tumor tissues of adriamycin-resistant breast cancer patients is also significantly higher than that in adriamycin-sensitive patients. The IC50 (Inhibitory Concentration 50). Of Adriamycin was significantly lower in FPRL2 silenced cells than those control cells. The apoptosis was markedly increased in FPRL2-silenced cells. p-ERK5 and p-AKT in breast cancer cells was significantly reduced after FPRL2 knocked down. In Conclusion, FPRL2 mediates Adriamycin resistance in breast cancer cells, and knockdown of FPRL2 increased apoptosis and decreased Adriamycin resistance in breast cancer cells.

11C]MK-6884 PET imaging reveals lower M4 muscarinic acetylcholine receptor availability following cocaine self-administration in male rats.

Cocaine Use Disorder (CUD) remains a significant problem in the United States, with high rates of relapse and no present FDA-approved treatment. The acetylcholine neurotransmitter system, specifically through modulation of muscarinic acetylcholine receptor (mAChR) function, has shown promise as a therapeutic target for multiple aspects of CUD. Enhancement of the M4 mAChR subtype via positive allosteric modulation has been shown to inhibit the behavioral and neurochemical effects of cocaine across several rodent models of CUD. However, it is unclear how cocaine exposure affects M4 mAChR expression or distribution. To evaluate the effects of cocaine self-administration on M4 mAChR availability using [11C]MK-6884 in vivo PET imaging in rats that self-administered cocaine (cocaine SA) or sucrose pellets (control). Sprague-Dawley rats self-administered cocaine or sucrose pellets for 15 days under 2-h or 4-h sessions followed by PET imaging with [11C]MK-6884, a radiolabeled M4 selective positive allosteric modulator to determine the effects of cocaine on [11C]MK-6884 standard uptake values with cerebellum as reference (SUVr). Cumulative cocaine intake ranged between 324 and 776mg/kg. Cocaine self-administration was associated with significantly lower [11C]MK-6884 SUVrs in the cortex, hippocampus, and striatum compared to cocaine-naive rats, with a negative correlation between radiotracer SUVrs and cocaine intake in the hippocampus. These results suggest that cocaine self-administration decreases M4 mAChR availability, providing further support for pursuing activation/enhancement of M4 mAChR function as a viable pharmacotherapeutic approach for CUD.

Conformational diversity in class C GPCR positive allosteric modulation

The metabotropic glutamate receptors (mGlus) are class C G protein-coupled receptors (GPCR) that form obligate dimers activated by the major excitatory neurotransmitter L-glutamate. The architecture of mGlu receptor comprises an extracellular Venus-Fly Trap domain (VFT) connected to the transmembrane domain (7TM) through a Cysteine-Rich Domain (CRD). The binding of L-glutamate in the VFTs and subsequent conformational change results in the signal being transmitted to the 7TM inducing G protein binding and activation. The mGlu receptors signal transduction can be allosterically potentiated by positive allosteric modulators (PAMs) binding to the 7TMs, which are of therapeutic interest in various neurological disorders. Here, we report the cryoEM structures of metabotropic glutamate receptor 5 (mGlu5) purified with three chemically and pharmacologically distinct PAMs. We find that the PAMs modulate the receptor equilibrium through their different binding modes, revealing how their interactions in the 7TMs impact the mGlu5 receptor conformational landscape and function. In addition, we identified a PAM-free but agonist-bound intermediate state that also reveals interactions mediated by intracellular loop 2. The activation of mGlu5 receptor is a multi-step process in which the binding of the PAMs in the 7TM modulates the equilibrium towards the active state.

Ganaxolone: A Review in Epileptic Seizures Associated with Cyclin-Dependent Kinase-Like 5 Deficiency Disorder.

Oral ganaxolone (ZTALMY®), a synthetic analogue of the endogenous neuroactive steroid allopregnanolone, acts as a positive allosteric modulator of synaptic and extra-synaptic γ-aminobutyric acid(GABA) type A receptor function in the CNS. In the EU and the UK, it is approved for the adjunctive treatment of epileptic seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients aged 2-17 years. In a multinational phase III study (Marigold), 17weeks' therapy with adjunctive ganaxolone, administered orally three times daily with food, significantly reduced 28-day major motor seizure frequency from baseline versus placebo in patients aged 2-19years with CDD-associated refractory epilepsy. Antiepileptic efficacy was generally sustained through 2years of treatment. Ganaxolone was generally well tolerated in Marigold. While somnolence and sedation are related to the dose of ganaxolone, they appear early in treatment and may decrease with continued therapy. Thus, although current evidence is somewhat limited,adjunctive ganaxolone could be a valuable therapeutic option for patients aged 2-17years with epileptic seizures associated with CDD.

The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases

Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals. We detected 359 significant associations between cytokine levels and variants in 169 independent loci, including 150 trans- and 19 cis-acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of the Atypical Chemokine Receptor 1 (ACKR1) acting as scavenger for multiple chemokines and the role of tumor necrosis factor receptor-associated factor 1 (TRAFD1) in modulating the cytokine storm triggered by TNF signaling. Applying Mendelian randomization (MR), we detected a network of complex cytokine interconnections with TNF-b, VEGF, and IL-1ra exhibiting pleiotropic downstream effects on multiple cytokines. Drug target cis-MR using 2 independent proteomics datasets paired with colocalization revealed G-CSF/CSF-3 and CXCL9/MIG as potential causal mediators of asthma and Crohn’s disease, respectively, but also a potentially protective role of TNF-b in multiple sclerosis. Our results provide an overview of the genetic architecture of circulating cytokines and could guide the development of targeted immunotherapies.

Sarcolemma resilience and skeletal muscle health require O-mannosylation of dystroglycan

BackgroundMaintaining the connection between skeletal muscle fibers and the surrounding basement membrane is essential for muscle function. Dystroglycan (DG) serves as a basement membrane extracellular matrix (ECM) receptor in many cells, and is also expressed in the outward-facing membrane, or sarcolemma, of skeletal muscle fibers. DG is a transmembrane protein comprised of two subunits: alpha-DG (α-DG), which resides in the peripheral membrane, and beta-DG (β-DG), which spans the membrane to intracellular regions. Extensive post-translational processing and O-mannosylation are required for α-DG to bind ECM proteins, which is mediated by a glycan structure known as matriglycan. O-mannose glycan biosynthesis is initiated by the protein O-mannosyltransferase 1 (POMT1) and POMT2 enzyme complex and leads to three subtypes of glycans called core M1, M2, and M3. The lengthy core M3 is capped with matriglycan. Genetic defects in post-translational O-mannosylation of DG interfere with its receptor function and result in muscular dystrophy with central nervous system and skeletal muscle pathophysiology.MethodsTo evaluate how the loss of O-mannosylated DG in skeletal muscle affects the development and progression of myopathology, we generated and characterized mice in which the Pomt1 gene was specifically deleted in skeletal muscle (Pomt1skm) to interfere with POMT1/2 enzyme activity. To investigate whether matriglycan is the primary core M glycan structure that provides the stabilizing link between the sarcolemma and ECM, we generated mice that retained cores M1, M2, and M3, but lacked matriglycan (conditional deletion of like-acetylglucosaminyltransferase 1; Large1skm). Next, we restored Pomt1 using gene transfer via AAV2/9-MCK-mPOMT1 and determined the effect on Pomt1skm pathophysiology.ResultsOur data showed that in Pomt1skm mice O-mannosylated DG is required for sarcolemma resilience, remodeling of muscle fibers and muscle tissue, and neuromuscular function. Notably, we observed similar body size limitations, sarcolemma weakness, and neuromuscular weakness in Large1skm mice that only lacked matriglycan. Furthermore, our data indicate that genetic rescue of Pomt1 in Pomt1skm mice limits contraction-induced sarcolemma damage and skeletal muscle pathology.ConclusionsCollectively, our data indicate that DG modification by Pomt1/2 results in core M3 capped with matriglycan, and that this is required to reinforce the sarcolemma and enable skeletal muscle health and neuromuscular strength.

Human α10 nicotinic acetylcholine receptor subunits assemble to form functional receptors.

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. In mammals, there are 16 individual nAChR subunits allowing for numerous possible heteromeric compositions. nAChRs assembled from α7 or α9 subunits will form as homopentamers. In contrast, the structurally related α10 nAChR subunit has historically been thought to require α9 subunits for function. Recently, however, strychnine was shown to enable expression of human α10 nAChRs in Xenopus laevis oocytes or mammalian cells, prompting a re-examination of whether the human α10 subunit can self-assemble in the absence of strychnine. In the present study, acetylcholine-evoked ionic currents were obtained by co-expression of human α10 nAChR subunits with the transmembrane protein resistance to inhibitors of cholinesterase-3 (RIC-3) in Xenopus oocytes. Furthermore, creation of a gain-of-function reporter mutation, V13'T, in the second transmembrane domain demonstrated that α10 subunits can self-assemble in the presence or absence of RIC-3. The antagonist sensitivity of the homomeric α10 nAChR is distinct from that of the closely related α7 and α9α10 subtypes. α10 homomers were blocked by α-bungarotoxin but were insensitive to α-conotoxin [V11L;V16D]ArIB and RgIA-5474, which potently block α7 nAChRs and α9α10 nAChRs, respectively. These studies yield insight into the assembly of functional human α10 homomers and provide tools for the development of α10 -nAChR-selective ligands.

Enhanced CB1 receptor function in GABAergic neurons mediates hyperexcitability and impaired sensory-driven synchrony of cortical circuits in Fragile X Syndrome model mice.

Electroencephalographic (EEG) recordings in individuals with Fragile X Syndrome (FXS) and the mouse model of FXS ( Fmr1 KO) display cortical hyperexcitability at rest, as well as deficits in sensory-driven cortical network synchrony. A form of circuit hyperexcitability is observed in ex vivo cortical slices of Fmr1 KO mice as prolonged persistent activity, or Up, states. It is unknown if the circuit mechanisms that cause prolonged Up states contribute to FXS-relevant EEG phenotypes. Here we examined the role of endocannabinoids (eCB) in prolonged Up states in slices and resting and sensory-driven EEG phenotypes in awake Fmr1 KO mice. Bidirectional changes in eCB function are reported in the Fmr1 KO that depend on synapse type (excitatory or inhibitory). We demonstrate that pharmacological or genetic reduction of Cannabinoid Receptor 1 (CB1R) in GABAergic neurons rescues prolonged cortical Up states and deficits in sensory-driven cortical synchrony in Fmr1 KO mice. In support of these findings, recordings from Fmr1 KO cortical Layer (L) 2/3 pyramidal neurons revealed enhanced CB1R-mediated suppression of inhibitory synaptic currents. In contrast, genetic reduction of Cnr1 in glutamatergic neurons did not affect Up state duration, but deletion of Fmr1 in the same neurons was sufficient to cause long Up states. These findings support a model where loss of Fmr1 in glutamatergic neurons leads to enhanced CB1R-mediated suppression of GABAergic synaptic transmission, prolonged cortical circuit activation and reduced sensory-driven circuit synchronization. Results suggest that antagonism of CB1Rs as a therapeutic strategy to correct sensory processing deficits in FXS.

The scent of habitat shift: Olfactory receptor evolution is associated with environmental transitions in turtles.

The transition between aquatic and terrestrial habitats leads to extreme structural changes in sensorial systems. Olfactory receptors (OR) are involved in the detection of odorant molecules both in water and on land. Therefore, ORs are affected by evolutionary habitat transitions experienced by organisms. In this study, we used turtles, a group of vertebrates which inhabit many distinct environments, to explore whether functional olfactory gene receptor repertoires are correlated to habitat. We found that the proportion of class I vs class II functional olfactory receptor genes (used for waterborne odorant detection and volatile odorant detection, respectively) was closely linked to habitat. Fully terrestrial turtles had the largest proportion of class II functional receptor genes while marine turtles had a larger proportion of class I receptor genes. Freshwater turtles had more balanced numbers of class I and class II functional receptor genes, but showed a gradient of OR type proportions likely reflecting species-specific amphibious preferences. Interestingly, freshwater turtles had by far the largest number of functional OR genes compared to those in other habitats, challenging the hypothesis that secondary adaptions to water may have reduced OR repertoires in amniotes. Our study provides novel results which shed new light on the relationship between chemical communication and habitat.

Molecular mechanisms of the GABA type A receptor function.

The GABA type A receptor (GABAAR) belongs to the family of pentameric ligand-gated ion channels and plays a key role in inhibition in adult mammalian brains. Dysfunction of this macromolecule may lead to epilepsy, anxiety disorders, autism, depression, and schizophrenia. GABAAR is also a target for multiple physiologically and clinically relevant modulators, such as benzodiazepines (BDZs), general anesthetics, and neurosteroids. The first GABAAR structure appeared in 2014, but the past years have brought a particularly abundant surge in structural data for these receptors with various ligands and modulators. Although the open conformation remains elusive, this novel information has pushed the structure-function studies to an unprecedented level. Electrophysiology, mutagenesis, photolabeling, and in silico simulations, guided by novel structural information, shed new light on the molecular mechanisms of receptor functioning. The main goal of this review is to present the current knowledge of GABAAR functional and structural properties. The review begins with an outline of the functional and structural studies of GABAAR, accompanied by some methodological considerations, especially biophysical methods, enabling the reader to follow how major breakthroughs in characterizing GABAAR features have been achieved. The main section provides a comprehensive analysis of the functional significance of specific structural elements in GABAARs. We additionally summarize the current knowledge on the binding sites for major GABAAR modulators, referring to the molecular underpinnings of their action. The final chapter of the review moves beyond examining GABAAR as an isolated macromolecule and describes the interactions of the receptor with other proteins in a broader context of inhibitory plasticity. In the final section, we propose a general conclusion that agonist binding to the orthosteric binding sites appears to rely on local interactions, whereas conformational transitions of bound macromolecule (gating) and allosteric modulation seem to reflect more global phenomena involving vast portions of the macromolecule.

Targeting FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia: Novel molecular approaches and therapeutic challenges.

Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, has generally a poor prognosis despite the recent advancements in diagnostics and treatment. Genetic instability, particularly mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, is associated with severe outcomes. Approximately 30 % of AML patients harbor FLT3 mutations, which have been linked to higher relapse and reduced survival rates. Traditional AML treatments employ cytarabine and anthracyclines drugs. Furthermore, the development of FLT3 inhibitors has significantly improved therapy for FLT3-mutated AML patients. For example, the introduction of midostaurin, the first FLT3 inhibitor, improved patient outcomes. However, resistant AML cell clones continue to pose a challenge to the success of AML treatment.This review discusses FLT3 kinase, mutations, and role in AML pathogenesis. It explores the molecular mechanisms of FLT3 activation, signaling pathways, and the structure and function of the FLT3 receptor. Current and emerging therapeutic approaches are presented, while highlighting the latest FLT3 inhibitors in clinical use, and strategies to overcome drug resistance. Future directions, including personalized therapies and novel drug designs, are examined to provide updated insights into FLT3-targeted treatments. This comprehensive review aims to guide clinicians and researchers in the development of innovative therapies to improve AML patient outcomes.

Gestational diabetes causes hyperactivity of the sympathetic nervous system and hypertension in adult mice offspring

ABSTRACT Background Gestational diabetes can lead to increased blood pressure in offspring, accompanied by impaired renal sodium excretion function and vasoconstriction and diastole dysfunction. However, there are few studies on whether it is accompanied by increased sympathetic nerve activity. Methods Pregnant C57BL/6 mice were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at day 0 of gestation. The mice of control mother offspring (CMO) and diabetic mother offspring (DMO) at 16 weeks of age were infused with vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h) or tempol (1 mmol/L, 0.4 μL/h) into the bilateral paraventricular nucleus (PVN) of mice for 4 weeks, respectively. Results Compared with CMO group, SBP and peripheral sympathetic nerve activity (increased heart rate, LF/HF and plasma norepinephrine and decreased SDNN and RMSSD) were increased in DMO group, which was accompanied by increased angiotensin II type-1 receptor (AT1R) expression and function in PVN. The increase in AT1R expression levels was attributed to a decrease in the methylation level of the AT1R promoter region, resulting in an increase in AT1R mRNA levels in PVN of DMO. Moreover, compared with CMO group, the levels of oxidative stress were increased and DNMT1 expression was decreased in PVN of DMO. Bilateral PVN infusion of tempol attenuated oxidative stress increased the level of DNMT1 expression and the binding of DNMT1 to the AT1R promoter region, which reduced mRNA and protein expression level of AT1R, heart rate and SBP in DMO, but not in CMO. Conclusions The present study provides evidence for overactive sympathetic nervous systems in the pathogenesis of gestational diabetes-induced hypertension in offspring. Central antioxidant intervention in the PVN may be an important treatment strategy for fetal-programmed hypertension.

Investigation the functions of membrane progesterone receptors using their selective ligands

Progesterone plays a key role in reproductive processes in the female body and has effects in the central nervous system and other tissues. Progestins are widely used clinically in contraception and hormonal therapy. The classical effects of progesterone are mediated through nuclear receptors, which are ligand-dependent transcription factors. Since 2003, membrane progesterone receptors (mPRs) of the adiponectin receptor family of five subtypes have been in the spotlight. Their role in many normal and pathological processes in the body remains unclear. Determining the mechanisms of action of progesterone is complicated by the fact that activation of different types of receptors can cause opposite effects. The search for selective ligands of mPRs is an important task, since the use of such compounds makes it possible to differentiate the effects of progestins mediated by different types of receptors. The review analyzes the action of three selective ligands of mPRs, described and studied at present. One of them is widely used in international research, the other two have been identified and used in our work. The advantages and defects of these three compounds and the studies of mPRs functions conducted using them are considered. In conclusion, the prospects for creating new selective mPRs ligands are assessed, taking into account the structural features of their ligand-binding pocket. We found that the 3-keto group of progesterone and its derivatives, which is fundamentally required for binding to nuclear steroid receptors, is not important for interaction with mPRs. Our conclusion was confirmed in a study published in 2022 using modeling techniques and mutational analysis. It is this structural feature that will further serve as the basis for the development of the synthesis of compounds that are effective and selectively interact with mPRs.

Structural and functional determination of peptide versus small molecule ligand binding at the apelin receptor

We describe a structural and functional study of the G protein-coupled apelin receptor, which binds two endogenous peptide ligands, apelin and Elabela/Toddler (ELA), to regulate cardiovascular development and function. Characterisation of naturally occurring apelin receptor variants from the UK Genomics England 100,000 Genomes Project, and AlphaFold2 modelling, identifies T892.64 as important in the ELA binding site, and R1684.64 as forming extensive interactions with the C-termini of both peptides. Base editing to introduce an R/H1684.64 variant into human stem cell-derived cardiomyocytes demonstrates that this residue is critical for receptor binding and function. Additionally, we present an apelin receptor crystal structure bound to the G protein-biased, small molecule agonist, CMF-019, which reveals a deeper binding mode versus the endogenous peptides at lipophilic pockets between transmembrane helices associated with GPCR activation. Overall, the data provide proof-of-principle for using genetic variation to identify key sites regulating receptor-ligand engagement.

Disrupting SARS-CoV-2 Spike Protein Activity: A Virtual Screening and Binding Assay Study

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a respiratory virus that emerged in late 2019 and rapidly spread worldwide, causing the COVID-19 pandemic. The spike glycoprotein (S protein) plays a crucial role in viral target recognition and entry by interacting with angiotensin, converting enzyme 2 (ACE2), the functional receptor for the virus, via its receptor binding domain (RBD). The RBD availability for this interaction can be influenced by external factors, such as fatty acids. Linoleic acid (LA), a free fatty acid, has been shown to bind the S protein, modulating the viral infection by reducing initial target recognition. LA interacts with the fatty acid binding pocket (FABP), a potential drug target against SARS-CoV-2. In this study, we aimed to exploit the FABP as a drug target by performing a docking-based virtual screening with a library of commercially available, drug-like compounds. The virtual hits identified were then assessed in in vitro assays for the inhibition of the virus–host interaction and cytotoxicity. Binding assays targeting the spike–ACE2 interaction identified multiple compounds with inhibitory activity and low cytotoxicity.

Targeting Tiam1 enhances hippocampal-dependent learning and memory in the adult brain and promotes NMDA receptor-mediated synaptic plasticity and function.

Excitatory synapses and the actin-rich dendritic spines on which they reside are indispensable for information processing and storage in the brain. In the adult hippocampus, excitatory synapses must balance plasticity and stability to support learning and memory. However, the mechanisms governing this balance remain poorly understood. Tiam1 is an actin cytoskeleton regulator prominently expressed in the dentate gyrus (DG) throughout life. Previously, we showed that Tiam1 promotes dentate granule cell synapse and spine stabilization during development, but its role in the adult hippocampus remains unclear. Here, we deleted Tiam1 from adult forebrain excitatory neurons (Tiam1fKO ) and assessed the effects on hippocampal-dependent behaviors. Adult male and female Tiam1fKO mice displayed enhanced contextual fear memory, fear extinction, and spatial discrimination. Investigation into underlying mechanisms revealed that dentate granule cells from Tiam1fKO brain slices exhibited augmented synaptic plasticity and NMDA-type glutamate receptor (NMDAR) function. Additionally, Tiam1 loss in primary hippocampal neurons blocked agonist-induced NMDAR internalization, reduced filamentous actin levels, and promoted activity-dependent spine remodeling. Notably, strong NMDAR activation in wild-type hippocampal neurons triggered Tiam1 loss from spines. Our results suggest that Tiam1 normally constrains hippocampal-dependent learning and memory in the adult brain by restricting NMDAR-mediated synaptic plasticity in the DG. We propose that Tiam1 achieves this by limiting NMDAR availability at synaptic membranes and stabilizing spine actin cytoskeleton, and that these constraints can be alleviated by activity-dependent degradation of Tiam1. These findings reveal a previously unknown mechanism restricting hippocampal synaptic plasticity and highlight Tiam1 as a therapeutic target for enhancing cognitive function.Significance statement The precise and dynamic regulation of excitatory synapses within hippocampal circuits is indispensable for learning and memory. These specialized connections must remain malleable to support the acquisition of relevant new information, but stable enough to protect the loss of previously stored memories. Dysregulation of this intricate balance drives cognitive decline following central nervous system injury and disease. Here, we establish the Rac1 guanine nucleotide exchange factor Tiam1 as an essential regulator of this balance that functions in the adult hippocampus to limit learning and memory. Our findings identify a previously unknown mechanism for restricting hippocampal synaptic plasticity that represents a potential therapeutic target for improving cognitive function.

Unveiling insect olfaction: advances and applications of electroantennography and single sensillum recording

Abstract Electroantennography (EAG) and single sensillum recording (SSR) are two fundamental electrophysiological techniques used to study the olfactory responses of insects. These methods have significantly contributed to our understanding of insect olfaction, from the initial identification of pheromones to the detailed analysis of olfactory receptor function. This review discusses the principles, methodologies and applications of EAG and SSR, highlighting their respective advantages and limitations. It also explores advancements in these techniques, such as multidimensional EAG, which offers an advanced approach to analysing complex odour mixtures. Emphasis is placed on the equipment, insect preparation, and technical considerations essential for effective electrophysiological studies. Keywords: Electroantennography (EAG), Single Sensillum Recording (SSR), Insect Olfaction, Olfactory Receptor Function, Multidimensional EAG.

Mechanism of Viral Immune Evasion

This article explores how viruses evade the host’s immune system through various mechanisms. Initially, the article introduces the innate immune system as the first line of defense against pathogens, activating an immune response by recognizing pathogen-associated molecular patterns (PAMPs). However, viruses such as HIV-1, Ebola virus (EBOV), and members of the Herpesviridae family have developed complex strategies to circumvent these defense mechanisms.HIV-1 evades the immune system by integrating into the host genome to form latent infections, exhibiting high genetic variability, and through cell-to-cell transmission. Ebola virus suppresses the function of pattern recognition receptors (PRRs), such as RIG-I and MDA5, and interferes with signaling pathways through its VP35 and VP24 proteins, thereby inhibiting the production of interferons (IFNs). Members of the Herpesviridae family evade the host’s innate immune response by interfering with PRRs, degrading immune factors, inducing post-translational modifications (PTMs), utilizing molecular sink strategies, and inhibiting the production of type I interferons and pro-inflammatory cytokines.The article emphasizes that a deep understanding of these viral immune evasion mechanisms is crucial for the development of effective antiviral therapies and vaccines.