Postsynaptic Receptors Research Articles

Possible Mechanisms of the Influence of Oxytocin and Vazopressin on Perception and Memory of Odors and on Social Behavior

A possible mechanism is proposed for the influence of oxytocin and vasopressin on the functioning of the neural network in the CNS, in which olfactory information is processed and stored, and which plays an important role in social behavior. The effect of these neuropeptides on postsynaptic receptors associated with Gq/11 proteins contributes to the induction of LTP of the efficacy of excitatory synaptic inputs to the main projection cells and to inhibitory interneurons in the prefrontal cortex, hippocampus, piriform cortex, anterior olfactory nucleus, olfactory bulb and nucleus accumbens, including the olfactory tubercle. As a result of disynaptic inhibition in each of the structures, the signal-to-noise ratio is improved and the transmission of strong signals through projection neurons to their target cells is facilitated. Due to the fact, that oxytocin promotes the release of dopamine by the neurons of the ventral tegmental area, the conditions for processing and memorizing olfactory information in the interconnected olfactory and hippocampal neural networks, including cortical and subcortical structures, are improved, and attention is also included in this processing. Long-term modification of the effectiveness of interneuronal connections in these networks under the influence of oxytocin and dopamine contributes to the formation and stabilization of contrasting neuronal representation of odors formed in cortical areas. Orientation of attention increases the significance of socially important olfactory stimuli and improves the conditions for the functioning of the reinforcement system necessary for adequate social behavior. Taking into account the known data on the correlation between social behavior and the density of oxytocin and vasopressin receptors on neurons of different structures, understanding the mechanisms of the influence of these neuropeptides on the functioning of the olfactory system can be useful for finding ways to correct behavior if necessary.

Efficacy and utility of isocycloseram a novel isoxazoline insecticide against urban pests and public health disease vectors

AbstractBACKGROUNDIsoxazolines inhibit γ‐aminobutyric acid chloride channels in insects and acarids by binding to postsynaptic receptors. This prevents chloride influx, leading to depolarization/hyperexcitation, paralysis, and death. Here, we evaluated the potential utility of a novel isoxazoline, isocycloseram, against several urban insect pests.RESULTSIsocycloseram was active at low doses against the German cockroach, Blattella germanica (L.) [median lethal dose (LD50) 5–15 ng per insect at 72 h, topical assays]; Argentine ant (Linepithema humile Mayr), Pharaoh ant (Monomorium pharaonis (L.), common bed bug (Cimex lectularius (L.) (approximately 40 mg m−2, residual surface spray); Eastern subterranean termite (Reticulitermes flavipes (Kollar) and Formosan subterranean termite (Coptotermes formosanus Shiraki) (5 μg g−1 w/w, tunneling assays); and mosquito, Anopheles stephensi Liston (120 and 150 mg m−2 treated surfaces, aged indoors for 9 months). Additionally, cockroach gel bait at 1% isocycloseram (w/w) caused 95–100% mortality in German, American (Periplaneta americana (L.), and oriental (Blatta orientalis (L.) cockroaches within 5–14 days.CONCLUSIONSIsocycloseram proved to be active against both laboratory and field populations of German cockroaches at doses lower or equal to those of other chemicals. Ants, bed bugs, and mosquitoes readily acquired lethal doses of isocycloseram from different surfaces treated with formulated products. Given its non‐repellent nature, delayed effects, and activity at low rates, isocycloseram can be a very effective compound against subsocial, social, and other human disease vector insect pests. © 2024 Society of Chemical Industry.

CNSC-43. NEUROTRANSMITTER DEPENDENCY UNDERLIES TUMOR GROWTH IN HUMANIZED PEDIATRIC LOW-GRADE GLIOMA MODELS

Abstract Brain tumors arise in close association with neurons, suggesting that these non-neoplastic cells may be critical stromal drivers of brain tumor initiation and growth. Previously, we have shown that murine low-grade optic glioma formation and progression in the setting of Neurofibromatosis type 1 (NF1) is dictated by neurons and neuronal activity. In these studies, these neuronal dependencies reflected neuronal activity-driven enzymatic cleavage of a growth factor (neuroligin-3) from oligodendrocyte precursors cells (tumor initiation) or neuronal production of a paracrine factor to stimulate T cell support of optic glioma growth (tumor progression). Since neurons typically communicate with other neurons through neurotransmitters, we sought to explore the possibility that neurotransmitters operate to modulate low-grade glioma growth using humanized mouse models of pilocytic astrocytoma (PA). Leveraging single cell RNA sequencing of three independent sets of pediatric PAs, we identified neurotransmitter pathway enrichment in the tumor cells. This neurotransmitter pathway enrichment reflected aberrant expression of specific neurotransmitter receptors, which we confirmed in three independently generated PA tissue microarrays and in five distinct primary PA cell lines grown in vitro. Moreover, this aberrant neurotransmitter receptor expression established differential neurotransmitter PA growth dependencies in vitro. Importantly, interruption of neurotransmitter signaling in human PA xenografts attenuated tumor growth and ERK activation in Rag1-/- mice in vivo. Finally, we discovered crosstalk between neurotransmitter receptor and receptor tyrosine kinase signaling that revealed another target for therapeutic inhibition. Taken together, these findings elucidate a previously unknown neurotransmitter PA growth dependency amenable to therapeutic targeting.

TMIC-18. ROLE OF NEUROTRANSMITTERS IN GLIOBLASTOMA PATHOPHYSIOLOGY: EMERGING INSIGHTS

Abstract INTRODUCTION Glioblastoma (GBM) are the most common primary brain tumor in adults associated with a dismal patient outcome. While it is well-known that glutamatergic neurons can form functional synapses with glioblastoma cells to enhance tumor growth, lesser is known about the effects of activity of other neuronal types on glioblastoma biology, especially among different glioblastoma molecular subtypes. Here, we examined the effects of various neurotransmitters on the growth of glioblastoma cells characterized as classical, proneural and mesenchymal subtypes. METHODS Patient-derived glioblastoma cell lines were exposed to varying concentrations of different neurotransmitters and assessed for cell viability using CCK-8 assay. Transcriptomic data from TCGA (The Cancer Genome Atlas) database was analyzed for correlation of expression of neurotransmitter receptors (NTRs) with patient survival. Using IVY-GAP database, we compared the expression of NTRs at leading-edge versus tumor core of tumors to assess their possible involvement in cell migration and microenvironmental interactions. RESULTS Consistent with previous findings, we observed an increase in cell viability in all GBM cell lines after being incubated with L-glutamate. The classical subtype has a stronger growth response to L-glutamate compared to the other two subtypes. TCGA data revealed the expression of GRIK4 (glutamate ionotropic receptor kainate type subunit 4) as highest in the classical subtype as well as inversely correlated with worse patient survival in this GBM subtype, as opposed to proneural or mesenchymal patient groups. CCK8 assay also suggested that acetylcholine and dopamine increase glioblastoma cell growth. A subset of cholinergic and glutamatergic receptors (CHRM1, GRM2) was found upregulated in infiltrating/leading-edge regions of glioblastoma tumors compared to the tumor core, suggesting possible involvement in glioblastoma-neuron interactions. CONCLUSION Our findings suggest that GBM subtypes may differentially leverage neuro-modulatory mechanisms to support their growth. Future studies will investigate the differential neuronal responses in GBM subtypes using pharmacological/genetic approaches.

CNSC-39. INTEGRATED CLINICAL GENETIC ANALYSIS REVEALS NEUROTRANSMITTER RECEPTOR DYSREGULATION IN MENINGIOMAS CAUSING SEIZURE

Abstract Molecular correlates of seizures in meningioma remain unexplored. Previously, we identified MenG molecular grouping, wherein MenG C meningiomas recur more than MenG A or B. We therefore sought to identify molecular and clinical drivers of seizures in meningioma. We identified 144 primary supratentorial meningiomas, excluding those with pre-existing epilepsy. Whole exome sequencing assessed somatic mutation burden. Bulk RNA-sequencing identified differentially expressed genes and gene ontologies (GO). Immunohistochemistry confirmed protein levels. No differences in canonical gene mutation burden (NF2, TRAF7, AKT1, KLF4, SMO, SMARC) was found between seizure and non-seizure groups. MenG C tumors had higher seizure incidence compared to MenG A or B (p=0.03). Seizure causing meningiomas, though extra-axial, exhibited dysregulated neuronal signaling genes. GABAA receptor subunit genes GABRA3 and GABRG1 were downregulated in tumors causing seizure (Log2FC=-1.67, padj=0.014; Log2FC=-2.24, padj=0.009). Immunohistochemistry confirmed expression of GABRB2 subunit, the first documentation of GABA receptor expression in meningiomas. Neuropeptide Y Receptor Y1 (NPY1R) is downregulated in seizure causing meningiomas (Log2FC=-1.64, padj=0.002). NPY1R loss correlates is observed in mesial temporal lobe epilepsy and post-electroconvulsive shock mouse brains. In GO analysis, the terms “GABA signaling pathway,” “neuropeptide signaling,” “excitatory postsynaptic membrane potential,” and “ionotropic glutamate pathway,” were downregulated in meningiomas with seizure (padj<0.05). We assessed which alterations within MenG C tumors caused seizures by identifying genes associated with both seizure presentation and MenG C classification. Glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) is downregulated in MenG C tumors (Log2FC=-2.29, padj=6.02E-07) and seizure causing tumors (Log2FC=-1.75, padj=0.03). Clinically, patients experiencing pre-operative seizures more frequently had cerebral edema, non-homogenous enhancement, intratumoral calcification, higher MIB-1, atypical grade 1, reduced GCS, and ER presentation; they were less likely to have incidental or headache presentation (p<0.05 for all). MenG classification predicts seizure presentation whereas somatic mutation status does not. Meningiomas causing seizures show pathologic neurotransmitter receptor dysregulation.

CNSC-56. DIVERSE, FUNCTIONAL NEUROTRANSMITTER RECEPTOR EXPRESSION ON GLIOBLASTOMA CELLS ENABLES EXTENSIVE NEURON-TO-GLIOMA COMMUNICATION

Abstract Glioblastomas are invasive yet incurable brain tumors. Recent data have shown that glutamatergic neuron-to-glioma synapses drive glioblastoma proliferation and invasion. In this study, we set out to investigate whether glioblastoma could communicate with neurons via various neuron-derived neurotransmitters through a functional neurotransmitter receptor screening. For this purpose, we stably transduced glioblastoma cells with a genetically encoded calcium indicator and sequentially and locally applied eight different neurotransmitters to glioblastoma cells in neuron-glioma co-cultures. These neurotransmitters included acetylcholine, ATP, dopamine, glutamate, GABA, adrenaline, serotonin, and glycine. We observed functional responses to acetylcholine, glutamate, ATP, dopamine, indicating a potential role for diverse neuron-to-glioma communication. Further, we investigated in patient-derived xenograft models and human tissues the existence of putative neuron-to-glioma synapses that could signal via acetlycholine, ATP and dopamine. In conclusion, this study reveals that glioblastoma cells express a heterogeneous set of functional neurotransmitter receptors, which may facilitate neuron-to-tumor communication across broad neuronal populations and warrant further investigation into their role for tumor biology.

Response to amoxicillin and perampanel in infantile Alexander disease.

Type I Alexander disease (AxD) presents with paroxysmal neurodegeneration, refractory epilepsy, and encephalopathy in the first years of life and is associated with a poor prognosis. Although there is no treatment, mild symptomatic improvement has been reported in one case of adult Alexander treated with ceftriaxone, given its interaction with the mutant glial fibrillary acid protein (GFAP) responsible for the disease's pathogenesis. We describe a patient presenting with irritability starting at 2 months of age, initially attributed to gastroesophageal reflux. A ventriculoperitoneal shunt was placed at 3 months of age due to hydrocephalus secondary to aqueduct stenosis detected through an MRI scan, but the irritability persisted. At 5 months, a new brain MRI was performed due to irritability worsening, onset of abnormal ocular movements and seizures. In addition genetic testing was performed. AxD was diagnosed due to the mutation c.716G>A (p.Arg239His) in GFAP. Since irritability had worsened and had not responded to levomepromazine, treatment with amoxicillin (80 mg/kg/day) was attempted to modulate glutamate levels. The patient showed a striking improvement of irritability in 48 h that persisted over the next months. The patient had frequent daily seizures which did not respond to valproate, clonazepam, or phenobarbital. Perampanel, a postsynaptic AMPA receptor antagonist, was added to phenobarbital and he was seizure free for more than 3 months. Drugs modulating glutamate levels in the central nervous system, including β-lactam antibiotics and perampanel, may have an important role in the symptomatic treatment of AxD and other neurodegenerative diseases where glutamatergic excitotoxicity is a pathogenic determinant. PLAIN LANGUAGE SUMMARY: Alexander disease is a rare and serious condition that affects the brain, often leading to neurodegeneration (brain damage), seizures, and other problems in early childhood. The disease is caused by a mutation in a gene called GFAP. There is no cure, and current treatments mainly focus on relieving symptoms. This article discusses the case of a baby who showed signs of irritability and seizures from a young age. The baby was diagnosed with Alexander disease after brain scans and genetic testing. Despite treatment with various drugs, the baby continued to experience seizures and irritability. The doctors decided to try amoxicillin, a common antibiotic, because of its potential to help control the disease by affecting a brain chemical called glutamate. Surprisingly, the baby's irritability improved within 2 days of starting amoxicillin, and the improvement lasted for several months. However, the seizures persisted until another medication, perampanel, was added. This combination controlled the baby's seizures for over 3 months. Unfortunately, the baby passed away at 13 months due to complications from the disease. However, doctors believe that drugs like amoxicillin and perampanel could be promising treatments for managing symptoms of Alexander disease and other similar brain conditions in the future, especially where excess glutamate plays a role in the damage. This case suggests that these treatments may help control irritability and seizures, offering hope for better management of this challenging disease.

Cryo-electron tomographic investigation of native hippocampal glutamatergic synapses

Chemical synapses are the major sites of communication between neurons in the nervous system and mediate either excitatory or inhibitory signaling. At excitatory synapses, glutamate is the primary neurotransmitter and upon release from presynaptic vesicles, is detected by postsynaptic glutamate receptors, which include ionotropic AMPA and NMDA receptors. Here, we have developed methods to identify glutamatergic synapses in brain tissue slices, label AMPA receptors with small gold nanoparticles (AuNPs), and prepare lamella for cryo-electron tomography studies. The targeted imaging of glutamatergic synapses in the lamella is facilitated by fluorescent pre- and postsynaptic signatures, and the subsequent tomograms allow for the identification of key features of chemical synapses, including synaptic vesicles, the synaptic cleft, and AuNP-labeled AMPA receptors. These methods pave the way for imaging brain regions at high resolution, using unstained, unfixed samples preserved under near-native conditions.

Cryo-electron tomographic investigation of native hippocampal glutamatergic synapses.

Chemical synapses are the major sites of communication between neurons in the nervous system and mediate either excitatory or inhibitory signaling. At excitatory synapses, glutamate is the primary neurotransmitter and upon release from presynaptic vesicles, is detected by postsynaptic glutamate receptors, which include ionotropic AMPA and NMDA receptors. Here, we have developed methods to identify glutamatergic synapses in brain tissue slices, label AMPA receptors with small gold nanoparticles (AuNPs), and prepare lamella for cryo-electron tomography studies. The targeted imaging of glutamatergic synapses in the lamella is facilitated by fluorescent pre- and postsynaptic signatures, and the subsequent tomograms allow for the identification of key features of chemical synapses, including synaptic vesicles, the synaptic cleft, and AuNP-labeled AMPA receptors. These methods pave the way for imaging brain regions at high resolution, using unstained, unfixed samples preserved under near-native conditions.

Multimodal action of phosphodiesterase 5 inhibitors against neurodegenerative disorders: An update review.

Phosphodiesterase type 5 (PDE5) is an enzyme primarily found in the smooth muscle of the corpus cavernosum and also highly expressed in the substantia nigra, cerebellum, caudate, hippocampal regions and cerebellar purkinje cells, responsible for selectively breaking down cyclic guanosine monophosphate (cGMP) into 5'-GMP and regulate intracellular cGMP levels. As a second messenger, cyclic GMP enhances signals at postsynaptic receptors and triggers downstream effector molecules, leading to changes in gene expression and neuronal responses. Additionally, cGMP signaling transduction cascade, present in the brain, is also essential for learning and memory processes. Mechanistically, PDE5 inhibitors share structural similarities with cGMP, competitively binding to PDE5 and inhibiting cGMP hydrolysis. This action enhances the effects of nitric oxide, resulting in anti-inflammatory and neuroprotective effects. Neurodegenerative disorders entail the progressive loss of neuron structure, culminating in neuronal cell death, with currently available drugs providing only limited symptomatic relief, rendering neurodegeneration considered incurable. PDE5 inhibitors have recently emerged as a potential therapeutic approach for neurodegeneration, neuroinflammation, and diseases involving cognitive impairment. This review elucidates the principal roles of 3',5'-cyclic adenosine monophosphate (cAMP) and cGMP signaling pathways in neuronal functions, believed to play pivotal roles in the pathogenesis of various neurodegenerative disorders. It provides an updated assessment of PDE5 inhibitors as disease-modifying agents for conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, Huntington's disease, and neuroinflammation. The paper aims to review the current understanding of PDE5 inhibitors, which concurrently regulate both cAMP and cGMP signaling pathways, positing that they may exert complementary and synergistic effects in modifying neurodegeneration, thus presenting a novel direction in therapeutic discovery. Moreover, the review provides critical about biological functions, therapeutic potentials, limitations, challenges, and emerging applications of selective PDE5 inhibitors. This comprehensive overview aims to guide future academic and industrial endeavors in this field.

Harnessing Brain Plasticity: The Therapeutic Power of Repetitive Transcranial Magnetic Stimulation (rTMS) and Theta Burst Stimulation (TBS) in Neurotransmitter Modulation, Receptor Dynamics, and Neuroimaging for Neurological Innovations

Transcranial magnetic stimulation (TMS) methods have become exciting techniques for altering brain activity and improving synaptic plasticity, earning recognition as valuable non-medicine treatments for a wide range of neurological disorders. Among these methods, repetitive TMS (rTMS) and theta-burst stimulation (TBS) show significant promise in improving outcomes for adults with complex neurological and neurodegenerative conditions, such as Alzheimer’s disease, stroke, Parkinson’s disease, etc. However, optimizing their effects remains a challenge due to variability in how patients respond and a limited understanding of how these techniques interact with crucial neurotransmitter systems. This narrative review explores the mechanisms of rTMS and TBS, which enhance neuroplasticity and functional improvement. We specifically focus on their effects on GABAergic and glutamatergic pathways and how they interact with key receptors like N-Methyl-D-Aspartate (NMDA) and AMPA receptors, which play essential roles in processes like long-term potentiation (LTP) and long-term depression (LTD). Additionally, we investigate how rTMS and TBS impact neuroplasticity and functional connectivity, particularly concerning brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase receptor type B (TrkB). Here, we highlight the significant potential of this research to expand our understanding of neuroplasticity and better treatment outcomes for patients. Through clarifying the neurobiology mechanisms behind rTMS and TBS with neuroimaging findings, we aim to develop more effective, personalized treatment plans that effectively address the challenges posed by neurological disorders and ultimately enhance the quality of neurorehabilitation services and provide future directions for patients’ care.

Biased allosteric modulator of neurotensin receptor 1 reduces ethanol drinking and responses to ethanol administration in rodents

Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse is the 7th leading cause of premature death [1]. Despite this, there are currently only 3 FDA approved pharmacological approaches for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant use. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, physiological sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.

Integrated transcriptomic hypothalamic-pituitary-ovarian axis network analysis reveals the role of energy availability on egg production in layers

Energy is a crucial component for maintaining egg production in layers. The hypothalamic-pituitary-ovarian (HPO) axis is an energy-sensitive functional axis for follicle development, synthesis, and secretion of reproductive hormones, and plays a key role in modulating sustained ovulation in layers. To investigate the mechanism of integrated network regulation of the HPO axis under energy fluctuation, ninety Hy-line brown layers (265-day-old, 1.92 ± 0.02 kg) were randomly divided into three groups for an 17-day experiment: a control group (Con group) fed ad libitum from days 1 to 17, an energy deprived group (ED group) that was fed ad libitum from days 1 to 12 and then underwent a fasting period from days 13 to 17 to induce a pause in laying, and a re-fed group (Rf group) that fasted for seven days (specifically, days 1 to 5, day 7, and day 9), had ad libitum access to feed on days 6 and 8, and were continuously fed from days 10 to 17. Each treatment consisted of 10 replicates with 3 birds per replicate. The study found that energy deprivation significantly decreased reproductive performance such as egg laying rate, ovarian index, number of small yellow follicles (SYF), and normal hierarchical follicles (NHIE) (P < 0.05), which recovered after refeeding, indicating the importance of energy availability for sustained ovulation in layers. In addition, estradiol (E2), estradiol/progesterone ratio (E2/P4), and luteinizing hormone (LH) displayed changes similar to follicle number, whereas follicle-stimulating hormone (FSH) exhibited a contrasting pattern. Transcriptome analysis revealed that energy deprivation downregulated genes related to energy and appetite-regulated neurotransmitter receptors and neuropeptides in the hypothalamus. These signals combined to inhibit gonadotropin-releasing hormone (GnRH) secretion and subsequently downregulated the crucial genes responsible for synthesizing gonadotropins, gonadotropin releasing hormone receptor (GnRHR), and glycoprotein hormones alpha chain (CGA). Consequently, this suppression of the hypothalamus and pituitary affected ovarian function through ovarian steroidogenesis and the extracellular matrix (ECM)-receptor interaction. These findings suggest that energy deprivation inhibits the function of the HPO axis, leading to impaired follicle development and reduced egg production and that refeeding can partially restore these indicators.

Molecular signature underlying (R)-ketamine rapid antidepressant response on anhedonic-like behavior induced by sustained exposure to stress

Anhedonia induced by sustained stress exposure is a hallmark symptom of major depressive disorder (MDD) and in rodents, it can be accessed through the sucrose preference test (SPT). (R)-ketamine is a fast-acting antidepressant with less detrimental side effects and abuse liability compared to racemic ketamine. The present study combined high-throughput proteomics and network analysis to identify molecular mechanisms involved in chronic variable stress (CVS)-induced anhedonia and promising targets underlying (R)-ketamine rapid antidepressant response. Male Wistar rats were subjected to CVS for five weeks. Based on the SPT, animals were clustered into resilient or anhedonic-like (ANH) groups. ANH rats received a single dose of saline or (R)-ketamine (20 mg/kg, i.p.), which was proceeded by treatment response evaluation. After prefrontal cortex collection, proteomic analysis was performed to uncover the differentially expressed proteins (DEPs) related to both anhedonic-like behavior and pharmacological response. The behavioral assessment showed that the ANH animals had a significant decrease in SPT, and that (R)-ketamine responders showed a reversal of anhedonic-like behavior. On a molecular level, anhedonia-like behavior was associated with the downregulation of Neuronal Pentraxin Receptor (Nptxr) and Galectin−1 (Gal-1). These data reinforce a disruption in the inflammatory response, neurotransmitter receptor activity, and glutamatergic synapses in chronic stress-induced anhedonia. (R)-ketamine response-associated DEPs included novel potential targets involved in the modulation of oxidative stress, energetic metabolism, synaptogenesis, dendritic arborization, neuroinflammation, gene expression, and telomere length, converging to biological themes extensively documented in MDD physiopathology. Our data provide valuable insights into the molecular mechanisms underlying the response to (R)-ketamine and highlight these pathways as potential therapeutic targets for anhedonia. By addressing proteins involved in oxidative stress, energy metabolism, synaptogenesis, dendritic arborization, neuroinflammation, gene expression, and telomere length, we can target multiple key factors involved in the pathophysiology of MDD. Modulating these proteins could open avenues for novel therapeutic strategies and deepen our understanding of anhedonia, offering hope for improved outcomes in individuals facing this challenging condition. However, additional studies will be essential to validate these findings and further explore their therapeutic implications.

Discovery of BAY 2413555, First Selective Positive Allosteric Modulator of the M2 Receptor to Restore Cardiac Autonomic Balance.

Autonomic disbalance, i.e., sympathetic overactivation and parasympathetic withdrawal, is a causal driver of disease progression in heart failure. While sympatholytic drugs are established treatments, no drug therapy restoring vagal control of cardiac function is available. We report here the HTS-based discovery of a novel class of 1,8-naphthyridin-4(1H)-one carboxamides acting as positive allosteric modulators (PAMs) of the M2 muscarinic acetylcholine receptor (M2R). M2R is the main postsynaptic myocyte receptor regulating heart rate, electrical conduction, and contractile strength. Extensive optimization of the screening hit in terms of potency, permeation, metabolic stability, and solubility ultimately resulted in the discovery of the first-in-class clinical candidate BAY 2413555 (27). With an overall technical profile compatible with once-daily oral administration in a phase 1 study, no apparent effects on blood pressure, and a mechanism that largely preserves autonomic regulatory capacity, BAY 2413555 could be the tool to finally study the restoration of autonomic balance.

Time dependent changes in protein expression induced by intermittent theta burst stimulation in a cell line

BackgroundIntermittent Theta Burst Stimulation (iTBS), a non-invasive brain stimulation technique, is recognized for its ability to modulate cortical neuronal activity. However, its effects over time and the dynamics following stimulation are less well understood. Understanding the temporal dynamics of iTBS effects is essential for optimizing the timing and frequency of stimulation in therapeutic applications.ObjectiveThis study investigated the temporal changes in protein expression induced by iTBS in Neuro-2a cells.MethodsWe analyzed protein expression in retinoic acid-differentiated Neuro-2a cells at multiple time points — 0.5, 3, 6, 12, and 24 hours post-iTBS — using Western blot and immunocytochemistry techniques.ResultsOur findings reveal a significant early increase in neurotransmitter receptor subunits, neurotrophic factors, and cytoskeletal proteins within the first 0.5 hour following iTBS. Notably, proteins such as mGLuR1, NMDAR1, GABBR2, and β-tubulin III showed substantial increase in expression. However, the effects of iTBS on protein expression was not sustained at later timepoints.ConclusionOur results suggest that iTBS can transiently alter the expression of specific proteins in Neuro-2a cells. Future research should investigate the potential benefits of repeated stimulations within the early time window to refine iTBS interventions, potentially expanding their research and clinical applications.

General anesthesia activates a central anxiolytic center in the BNST

Low doses of general anesthetics like ketamine and dexmedetomidine have anxiolytic properties independent of their sedative effects, but the underlying mechanisms remain unclear. We discovered a population of GABAergic neurons in the oval division of the bed nucleus of the stria terminalis that are activated by multiple anesthetics and the anxiolytic drug diazepam (ovBNSTGA). The majority of ovBNSTGA neurons express neurotensin receptor 1 (Ntsr1) and form circuits with brain regions known to regulate anxiety and stress responses. Optogenetic activation of ovBNSTGA or ovBNSTNtsr1 neurons significantly attenuated anxiety-like behaviors in both naive animals and mice with inflammatory pain, while inhibition of these cells elevated anxiety. Activation of these neurons decreased heart rate and increased heart rate variability, suggesting that they reduce anxiety by modulating autonomic responses. Our study identifies ovBNSTGA/ovBNSTNtsr1 neurons as a common neural substrate mediating the anxiolytic effect of low-dose anesthetics and a potential therapeutic target for treating anxiety-related disorders.

Neurotensin receptor agonist PD149163 modulates the adrenal dysfunction in mice intraperitoneally treated with lipopolysaccharide from Escherichia coli O26:B6

Neurotensin receptor agonist PD149163 modulates the adrenal dysfunction in mice intraperitoneally treated with lipopolysaccharide from Escherichia coli O26:B6

The role of synaptic protein NSF in the development and progression of neurological diseases.

This document provides a comprehensive examination of the pivotal function of the N-ethylmaleimide-sensitive factor (NSF) protein in synaptic function. The NSF protein directly participates in critical biological processes, including the cyclic movement of synaptic vesicles (SVs) between exocytosis and endocytosis, the release and transmission of neurotransmitters, and the development of synaptic plasticity through interactions with various proteins, such as SNARE proteins and neurotransmitter receptors. This review also described the multiple functions of NSF in intracellular membrane fusion events and its close associations with several neurological disorders, such as Parkinson's disease, Alzheimer's disease, and epilepsy. Subsequent studies should concentrate on determining high-resolution structures of NSF in different domains, identifying its specific alterations in various diseases, and screening small molecule regulators of NSF from multiple perspectives. These research endeavors aim to reveal new therapeutic targets associated with the biological functions of NSF and disease mechanisms.

Modulation of heteromeric glycine receptor function through high concentration clustering.

Ion channels are targeted by many drugs for treating neurological, musculoskeletal, renal and other diseases. These drugs bind to and alter the function of individual channels to achieve desired therapeutic effects. However, many ion channels function in high concentration clusters in their native environment. It is unclear if and how clustering modulates ion channel function. Human heteromeric glycine receptors (GlyRs) are the major inhibitory neurotransmitter receptors in the spinal cord and are active targets for developing chronic pain medications. We show that the α2β heteromeric GlyR assembles with the master postsynaptic scaffolding gephyrin (GPHN) into micron-sized clustered at the plasma membrane after heterologous expression. The inhibitory trans- synaptic adhesion protein neuroligin-2 (NL2) further increases both the cluster sizes and GlyR concentration. The apparent glycine affinity increases monotonically as a function of GlyR concentration but not with cluster size. We also show that ligand re-binding to adjacent GlyRs alters kinetics but not chemical equilibrium. A positively charged N- terminus sequence of the GlyR β subunit was further identified essential for glycine affinity modulation through clustering. Taken together, we propose a mechanism where clustering enhances local electrostatic potential, which in turn concentrates ions and ligands, modulating the function of GlyR. This mechanism is likely universal across ion channel clusters found ubiquitously in biology and provides new perspectives in possible pharmaceutical development.