Excitatory Glutamatergic Neurotransmission Research Articles

Preso enhances mGluR1-mediated excitotoxicity by modulating the phosphorylation of mGluR1-Homer1 complex and facilitating an ER stress after traumatic brain injury

Glutamate receptor (GluR)-mediated excitotoxicity is an important mechanism causing delayed neuronal injury after traumatic brain injury (TBI). Preso, as a core scaffolding protein of postsynaptic density (PSD), is considered an important regulator during excitotoxicity and TBI and combines with glutamate receptors to form functional units for excitatory glutamatergic neurotransmission, and elucidating the mechanisms of these functional units will provide new targets for the treatment of TBI. As a multidomain scaffolding protein, Preso directly interacts with metabotropic GluR (mGluR) and another scaffold protein, Homer. Because the mGluR-Homer complex plays a crucial role in TBI, modulation of this complex by Preso may be an important mechanism affecting the excitotoxic damage to neurons after TBI. Here, we demonstrate that Preso facilitates the interaction between metabotropic mGluR1 and Homer1 to activate mGluR1 signaling and cause excitotoxic neuronal injury and endoplasmic reticulum (ER) stress after TBI. The regulatory effect of Preso on the mGluR1-Homer1 complex is dependent on the direct association between Preso and this complex and also involves the phosphorylation of the interactive binding sites of mGluR1 and Homer1 by Preso. Further studies confirmed that Preso, as an adaptor of cyclin-dependent kinase 5 (CDK5), promotes the phosphorylation of the Homer1-binding site on mGluR1 by CDK5 and thereby enhances the interaction between mGluR1 and Homer1. Preso can also promote the formation of the mGluR1-Homer1 complex by inhibiting the phosphorylation of the Homer1 hinge region by Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα). Based on these molecular mechanisms, we designed several blocking peptides targeting the interaction between Preso and the mGluR1-Homer1 complex and found that directly disrupting the association between mGluR1 and scaffolding proteins significantly promotes the recovery of motor function after TBI.

Restoration of nNOS Expression Rescues Autistic-Like Phenotypes Through Normalization of AMPAReceptor-Mediated Neurotransmission.

Autism spectrum disorder (ASD) is associated with a range of abnormalities characterized by deficits in socialization, communication, repetitive behaviors, and restricted interests. We have recently shown that neuronal nitric oxide synthase (nNOS) expression was decreased in the basolateral amygdala (BLA) of mice after postnatal valproic acid exposure. Neuronal activity-regulated pentraxin (Narp) could contribute to the regulation of the GluA4 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) subunits which are predominantly expressed in interneurons. However, the specific role of nNOS re-expression on excitatory neurotransmitter with relevance to ASDcore symptoms in VPA-treated animals remains to be elucidated. Herein, nNOS overexpression using a lentiviral vector and L-arginine-activating PI3K-Akt-mTOR signaling can restore nNOS expression in the BLA induced by VPA. Restoration of nNOS expression in these mice was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, stereotyped/repetitive behaviors, and anxiety-like traits. Most strikingly, re-expression of nNOS upregulated surface expression of Narp and GluA4 in nNOS-positive interneuron as shown by immunoprecipitation and Western blotting. Whole-cell patch-clamp recordings demonstrated that restoration of nNOS had a significant enhancing effect on AMPA receptor-mediated excitatory glutamatergic synaptic neurotransmission, which was inhibited by disturbing the interaction between Narp and GluA4 in acutelydissociated BLA slices. Overall, these data offer a scientific basis for the additional study of nNOS re-expression as a promising therapeutic target by correcting AMPA receptor-mediated synaptic function in ASD and related neurodevelopmental disorders.

Transcranial direct current stimulation combined with speech therapy in Fragile X syndrome patients: a pilot study.

Fragile X syndrome (FXS) is the leading cause of genetic intellectual disability. Among the neurobehavioral dysfunctions in FXS individuals, language development and literacy are compromised. Recent evidence hypothesized that the disruption of excitatory glutamatergic and GABAergic inhibitory neurotransmission balance might be responsible for impairment in cognitive function. In this study, we evaluated for the first time, the safety, tolerability, and efficacy of anodal prefrontal transcranial direct current stimulation (tDCS) combined with standard speech therapy to enhance language function in FXS patients. In total, 16 adult FXS patients were enrolled. Participants underwent 45 min of anodic tDCS combined with speech therapy for 5 weeks (3 times per week). Language function was evaluated using the Test for Reception of Grammar-Version 2 (TROG-2) and subtests of the Italian Language Examination (Esame del Linguaggio - II, EDL-II). Right and left dorsolateral prefrontal cortex transcranial magnetic stimulation and concurrent electroencephalography (TMS-EEG) recordings were collected at baseline and after the treatment to evaluate cortical reactivity and connectivity changes. After 5 weeks of combined therapy, we observed a significant improvement in the writing (7.5%), reading (20.3%), repetition (13.3%), and TROG-2 (10.2%) tests. Parallelly with clinical change, TMS-EEG results showed a significant difference in TMS-evoked potential amplitude over the left frontal cortex after treatment (-0.73 ± 0.87 μV) compared to baseline (0.18 ± 0.84 μV). Our study provides novel evidence that left anodal prefrontal tDCS combined with standard speech therapy could be effective in enhancing language function in FXS patients, mainly by inducing a rebalance of the dysfunctional prefrontal cortical excitability.

An In Vivo Electroencephalographic Analysis of the Effect of Riluzole against Limbic and Absence Seizure and Comparison with Glutamate Antagonists.

Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague-Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. In Sprague-Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors.

Differential Modulation of the Excitatory and Inhibitory Synaptic Circuits of Retinal Ganglion Cells via Asiatic Acid in a Chronic Glaucoma Rat Model.

To investigate whether asiatic acid (AA) can improve the quantity and function of retinal ganglion cells (RGCs), as well as how AA regulates synaptic pathways in rat models with chronic glaucoma. In our study, a rat model of chronic glaucoma was prepared via the electrocoagulation of the episcleral veins. The numbers of surviving RGCs were counted via retrograde Fluorogold labeling, and a whole-cell patch clamp was used to clamp RGCs in normal retinal sections and in retinal sections 4 weeks after glaucoma induction. Retrograde-Fluorogold-labeled RGC loss caused by persistent glaucoma was decreased by AA. Additionally, AA reduced the postsynaptic current produced by N-methyl-D-aspartate (NMDA) and diminished miniature glutamatergic excitatory neurotransmission to RGCs. On the other hand, AA increased miniature gamma-aminobutyric acid (GABA)-ergic inhibitory neurotransmission to RGCs and enhanced the GABA-induced postsynaptic current. The excitability of the RGC itself was also decreased by AA. RGCs in glaucomatous slices were less excitable because AA decreased their spontaneous action potential frequency and membrane potential, which led to a hyperpolarized condition. AA directly protected RGCs in a chronic glaucoma rat model by lowering their hyperexcitability. To enhance RGCs' survival and function in glaucoma, AA may be a viable therapeutic drug.

Cardiovascular toxin-induced hyperglycemic and hypoarousal pathology-associated cognitive impairment: an in silico and in vivo validation

Background and purpose: Medication-induced cardiotoxicity is a significant factor in the attrition of drugs during preclinical and clinical development processes. Patients with diabetes mellitus (hyperglycemic) are more than twice as likely to experience cardiac failure. Additionally, type 2 diabetes mellitus (T2D) patients often display significant hyperarousal-related clinical anomalies such as fear, panic, nervousness, pain, and seizures. Consequently, hyperarousal in patients with inadequate metabolic outcomes (hyperglycemic conditions) is usually treated with drugs that block sodium/calcium channels, augment inhibitory (gamma-aminobutyric acid [GABA]) neurotransmission, and reduce excitatory (glutamatergic) neurotransmission. These perilous combined clinical-pathological conditions of hyperglycemia and hypoarousal may result in severe learning disabilities and cognitive impairment. Unfortunately, only a few studies have investigated the synergistic effects of hypoarousal and hyperglycemia on cognition. Methods: General behavioral assessment, plus maze, Y-maze spontaneous alternation, Hebb-Williams maze and Passive avoidance paradigm were evaluated in this study. The current study assessed the in silico structural properties attributed to its pharmacodynamic actions and interaction with Gamma-aminobutyric acid (GABA) and insulin receptors using Schrodinger and LigPrep software. Results: The administration of alloxan and phenytoin induced significant learning and cognitive deficiencies. Based on the in silico studies, alloxan is a better drug to induce hyperglycemia as compared to the well-established hyperglycemic agent, streptozotocin (STZ). Conclusions: The current study indicated that administering alloxan and phenytoin to rodents can serve as a valid animal model to understand the pathophysiology associated with hypoarousal and hyperglycemia-mediated cognitive impairment and to identify novel therapeutic interventions for hyperglycemic and hypoarousal-related learning and cognitive deficiency.

Targeting NMDA Receptors in Emotional Disorders: Their Role in Neuroprotection.

Excitatory glutamatergic neurotransmission mediated through N-methyl-D-Aspartate (NMDA) receptors (NMDARs) is essential for synaptic plasticity and neuronal survival. While under pathological states, abnormal NMDAR activation is involved in the occurrence and development of psychiatric disorders, which suggests a directional modulation of NMDAR activity that contributes to the remission and treatment of psychiatric disorders. This review thus focuses on the involvement of NMDARs in the pathophysiological processes of psychiatric mood disorders and analyzes the neuroprotective mechanisms of NMDARs. Firstly, we introduce NMDAR-mediated neural signaling pathways in brain function and mood regulation as well as the pathophysiological mechanisms of NMDARs in emotion-related mental disorders such as anxiety and depression. Then, we provide an in-depth summary of current NMDAR modulators that have the potential to be developed into clinical drugs and their pharmacological research achievements in the treatment of anxiety and depression. Based on these findings, drug-targeting for NMDARs might open up novel territory for the development of therapeutic agents for refractory anxiety and depression.

Bioactivity guided fractionation of <em>Bombax ceib</em>a L. root extract for antidepressant activity and elucidation of mechanism of action using <em>in silico</em> studies

The glutamate system has received considerable attention in recent years as a target for development of novel therapeutics, including antidepressants. There are several lines of evidence showing the role of excitatory glutamatergic neurotransmission in depression and antidepressant activity of N-methyl D-aspartate (NMDA) antagonists like ketamine. The excitoxicity induced by glutamate receptor subtype NMDA is selectively and markedly inhibited by hesperidin. The hesperidin is one of the active constituents isolated from the roots of the cotton tree, Bombax ceiba L. (Bombacaceae) . In this context, here, we studied the antidepressant activity of ethanolic extract of root of B. ceiba and its fractions viz., chloroform fraction CBCR (200 & 400 mg/kg); ethyl acetate fraction EABCR (200 & 400 mg/kg); n-butanol fraction (200 & 400 mg/kg) using two animal models of learned helplessness. To further elucidate the possible NMDA antagonist effect of hesperetin, an active metabolite of hesperedin, in silico docking studies were carried out using 5VIH protein of Rattus norvegicus (Brown rat) which consists of GluN1/GluN2A NMDA receptor agonist binding domains, using Inventus v 1.1. Results of in silico study revealed good binding affinity of hesperetin to 5VIH protein. The data indicated antidepressant like activity of the extract and its fractions. The effect was more promising with ethyl acetate and n-butanol fraction of the extract which could be attributed to the antagonistic effect of hesperetin to GluN1/GluN2A NMDA receptor, present in roots of B. ceiba

Brain-Derived Neurotrophic Factor Inhibits the Function of Cation-Chloride Cotransporter in a Mouse Model of Viral Infection-Induced Epilepsy.

Well over 100 different viruses can infect the brain and cause brain inflammation. In the developing world, brain inflammation is a leading cause for epilepsy and often refractory to established anti-seizure drugs. Epilepsy generally results from an imbalance in excitatory glutamatergic and inhibitory GABAergic neurotransmission. GABAergic inhibition is determined by the intracellular Cl− concentration which is established through the opposing action of two cation chloride cotransporters namely NKCC1 and KCC2. Brain-derived neurotrophic factor (BDNF) signaling is known to regulate expression of KCC2. Hence we hypothesized that viral induced epilepsy may result from aberrant BDNF signaling. We tested this hypothesis using a mouse model of Theiler’s murine encephalomyelitis virus (TMEV) infection-induced epilepsy. We found that BDNF levels in the hippocampus from TMEV-infected mice with seizures was increased at the onset of acute seizures and continued to increase during the peak of acute seizure as well as in latent and chronic phases of epilepsy. During the acute phase of epilepsy, we found significant reduction in the expression of KCC2 in hippocampus, whereas the level of NKCC1 was unaltered. Importantly, inhibiting BDNF using scavenging bodies of BDNF in live brain slices from TMEV-infected mice with seizures normalized the level of KCC2 in hippocampus. Our results suggest that BDNF can directly decrease the relative expression of NKCC1 and KCC2 such as to favor accumulation of chloride intracellularly which in turn causes hyperexcitability by reversing GABA-mediated inhibition. Although our attempt to inhibit the BDNF signaling mediated through tyrosine kinase B–phospholipase Cγ1 (TrkB-PLCγ1) using a small peptide did not change the course of seizure development following TMEV infection, alternative strategies for controlling the BDNF signaling could be useful in preventing seizure generation and development of epilepsy in this model.

The role of neuronal excitation and inhibition in the pre-Bötzinger complex on the cough reflex in the cat.

Brainstem respiratory neuronal network significantly contributes to cough motor pattern generation. Neuronal populations in the pre-Bötzinger complex (PreBötC) represent a substantial component for respiratory rhythmogenesis. We studied the role of PreBötC neuronal excitation and inhibition on mechanically induced tracheobronchial cough in 15 spontaneously breathing, pentobarbital anesthetized adult cats (35 mg/kg, iv initially). Neuronal excitation by unilateral microinjection of glutamate analog d,l-homocysteic acid resulted in mild reduction of cough abdominal electromyogram (EMG) amplitudes and very limited temporal changes of cough compared with effects on breathing (very high respiratory rate, high amplitude inspiratory bursts with a short inspiratory phase, and tonic inspiratory motor component). Mean arterial blood pressure temporarily decreased. Blocking glutamate-related neuronal excitation by bilateral microinjections of nonspecific glutamate receptor antagonist kynurenic acid reduced cough inspiratory and expiratory EMG amplitude and shortened most cough temporal characteristics similarly to breathing temporal characteristics. Respiratory rate decreased and blood pressure temporarily increased. Limiting active neuronal inhibition by unilateral and bilateral microinjections of GABAA receptor antagonist gabazine resulted in lower cough number, reduced expiratory cough efforts, and prolongation of cough temporal features and breathing phases (with lower respiratory rate). The PreBötC is important for cough motor pattern generation. Excitatory glutamatergic neurotransmission in the PreBötC is involved in control of cough intensity and patterning. GABAA receptor-related inhibition in the PreBötC strongly affects breathing and coughing phase durations in the same manner, as well as cough expiratory efforts. In conclusion, differences in effects on cough and breathing are consistent with separate control of these behaviors.NEW & NOTEWORTHY This study is the first to explore the role of the inspiratory rhythm and pattern generator, the pre-Bötzinger complex (PreBötC), in cough motor pattern formation. In the PreBötC, excitatory glutamatergic neurotransmission affects cough intensity and patterning but not rhythm, and GABAA receptor-related inhibition affects coughing and breathing phase durations similarly to each other. Our data show that the PreBötC is important for cough motor pattern generation, but cough rhythmogenesis appears to be controlled elsewhere.

In vivo glucose metabolism and glutamate levels in mGluR5 knockout mice: a multimodal neuroimaging study using [18F]FDG microPET and MRS

BackgroundPerturbed functional coupling between the metabotropic glutamate receptor-5 (mGluR5) and N-methyl-d-aspartate (NMDA) receptor-mediated excitatory glutamatergic neurotransmission may contribute to the pathophysiology of psychiatric disorders such as schizophrenia. We aimed to establish the functional interaction between mGluR5 and NMDA receptors in brain of mice with genetic ablation of the mGluR5.MethodsWe first measured the brain glutamate levels with magnetic resonance spectroscopy (MRS) in mGluR5 knockout (KO) and wild-type (WT) mice. Then, we assessed brain glucose metabolism with [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography before and after the acute administration of an NMDA antagonist, MK-801 (0.5 mg/kg), in the same mGluR5 KO and WT mice.ResultsBetween-group comparisons showed no significant differences in [18F]FDG standardized uptake values (SUVs) in brain of mGluR5 KO and WT mice at baseline, but widespread reductions in mGluR5 KO mice compared to WT mice after MK-801 administration (p < 0.05). The baseline glutamate levels did not differ significantly between the two groups. However, there were significant negative correlations between baseline prefrontal glutamate levels and regional [18F]FDG SUVs in mGluR5 KO mice (p < 0.05), but no such correlations in WT mice. Fisher’s Z-transformation analysis revealed significant between-group differences in these correlations (p < 0.05).ConclusionsThis is the first multimodal neuroimaging study in mGluR5 KO mice and the first report on the association between cerebral glucose metabolism and glutamate levels in living rodents. The results indicate that mGluR5 KO mice respond to NMDA antagonism with reduced cerebral glucose metabolism, suggesting that mGluR5 transmission normally moderates the net effects of NMDA receptor antagonism on neuronal activity. The negative correlation between glutamate levels and glucose metabolism in mGluR5 KO mice at baseline may suggest an unmasking of an inhibitory component of the glutamatergic regulation of neuronal energy metabolism.

The glutamatergic system in the preoptic area is involved in the retention of maternal behavior in maternally experienced female rats.

Maternally experienced female rats show high maternal behavior performance for a long time after acquisition of maternal experience, although the mechanisms responsible for the retention of maternal behavior are not well understood. The medial preoptic area (MPOA) plays an important role in the onset and maintenance of maternal behavior in female rats. We aimed to determine whether maternal experience affects the glutamatergic system in the MPOA for the retention of maternal behavior in female rats. First, to determine the effects of maternal experience in the postpartum period on dendritic spines, which are the postsynaptic component of excitatory glutamatergic neurotransmission, we examined the number of dendritic spines on MPOA neurons of primiparous mothers that had experienced mothering until weaning (sufficiently experienced mothers) and of primiparous mothers that were separated from their pups on the day of parturition (insufficiently experienced mothers). The number of mushroom spines, but not other types of spine, was significantly greater in the sufficiently experienced mothers compared with that in the insufficiently experienced mothers. Next, to determine the effects of maternal experience in the postpartum period on the expression of ionotropic glutamate receptors, we measured the mRNA levels of AMPA receptor subunits (GluA1-A4) and NMDA receptor subunits (GluN1, GluN2A-2D) in the MPOA of primiparous female rats that were kept with pups until brain sampling. As a result, we found that the mRNA levels of GluA3 and GluN2B were significantly higher in primiparous females on the day of weaning compared with those in primiparous females on the day of parturition. Additionally, we examined the effects of CNQX, an AMPA receptor antagonist, and MK-801, an NMDA receptor antagonist, injected into the MPOA on maternal behavior in maternally experienced primiparous female rats. Maternal behavioral activity was significantly reduced when CNQX or MK-801 was injected into the MPOA. These findings indicate that long-term maternal experience in the postpartum period up-regulates glutamatergic neurotransmission by increasing the number of mushroom spines and glutamate receptor expression, which may be involved in the retention of maternal behavior in maternally experienced female rats.

Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia.

Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamine – glutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a co-agonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS.

ACC Glu/GABA ratio is decreased in euthymic bipolar disorder I patients: possible in vivo neurometabolite explanation for mood stabilization.

Bipolar disorder (BD) is characterized by unstable mood states ranging from mania to depression. Although there is some evidence that mood instability may result from an imbalance between excitatory glutamatergic and inhibitory GABA-ergic neurotransmission, few proton magnetic resonance spectroscopy (1H-MRS) studies have measured these two neurometabolites simultaneously in BD. The enzyme glutamic acid decarboxylase (GAD1) catalyzes the decarboxylation of glutamate (Glu) to GABA, and its single nucleotide polymorphisms (SNPs) might influence Glu/GABA ratio. Thus, we investigated Glu/GABA ratio in the dorsal anterior cingulate cortex (dACC) of euthymic BD type I patients and healthy controls (HC), and assessed the influence of both mood stabilizers and GAD1 SNPs on this ratio. Eighty-eight subjects (50 euthymic BD type I patients and 38 HC) underwent 3T 1H-MRS in the dACC (2 × 2×4.5 cm3) using a two-dimensional JPRESS sequence and all subjects were genotyped for 4 SNPs in the GAD1 gene. BD patients had lower dACC Glu/GABA ratio compared to HC, where this was influenced by anticonvulsant and antipsychotic medications, but not lithium. The presence of GAD1 rs1978340 allele A was associated with higher Glu/GABA ratio in BD, while patients without this allele taking mood stabilizers had a lower Glu/GABA ratio. The lowering of dACC Glu/GABA could be one explanation for the mood stabilizing action of anticonvulsants and antipsychotics in BD type I euthymia. Therefore, this putative role of Glu/GABA ratio and the influence of GAD1 genotype interacting with mood stabilization medication should be confirmed by further studies involving larger samples and other mood states.ClincalTrials.gov registration: NCT01237158.

The Pathogenesis of Fever-Induced Febrile Seizures and Its Current State

Febrile seizures, commonly in children between the ages of 3 months to 5 years, are a neurological abnormality characterized by neuronal hyper-excitability, that occur as a result of an increased core body temperature during a fever, which was caused by an underlying systemic infection. Such infections cause the immune system to elicit an inflammatory response resulting in the release of cytokines from macrophages. The cytokines such as interleukin (IL)- 1β, IL-6, and tumour necrosis factor-α (TNF-α) combat the infection in the localized area ultimately spilling over into circulation resulting in elevated cytokine levels. The cytokines, along with pathogen-associated molecular patterns (PAMPs) expressed on pathogens for example, lipopolysaccharide (LPS), interact with the blood brain barrier (BBB) causing a ‘leaky’ BBB which facilitates cytokines and LPS entry into the central nervous system. The cytokines activate the microglia which release their own cytokines, specifically IL1β. IL-β interacts with the brain endothelium resulting in the activation of cyclooxygenase 2 which catalyzes the production of prostaglandin 2 (PGE2). PGE2 enters the hypothalamic region and induces a fever. Abnormally increased IL-1β levels also progressively increases excitatory (glutamatergic) neurotransmission, and decreases inhibitory (GABAergic) neurotransmission, thus mediating the pathogenesis of convulsions. Current treatments for febrile seizures present with side effects that are detrimental to health, which fosters the need for an alternative, more affordable treatment with fewer adverse side effects, and 1 that is easily accessible, especially in low income areas that are also affected by other underlying socio-economic factors, in which febrile seizures are of growing concern.

Quercetin Enhances Inhibitory Synaptic Inputs and Reduces Excitatory Synaptic Inputs to OFF- and ON-Type Retinal Ganglion Cells in a Chronic Glaucoma Rat Model.

BackgroundGlaucoma is a neurodegenerative disease caused by excitotoxic injury of retinal ganglion cells (RGCs). In our previous model of high intraocular pressure, prepared by injecting magnetic beads into the anterior chamber, we demonstrated that an important natural dietary flavonoid compound (quercetin) can improve RGC function. However, it is unclear whether quercetin can improve the synaptic function of RGCs and how quercetin regulates synaptic transmission in rat models of chronic glaucoma.MethodsA rat model of chronic glaucoma was prepared by electrocoagulation of the superior scleral vein. Electrophysiological electroretinography was used to detect the photopic negative response (PhNR). The whole-cell patch-clamp technique was used to clamp ON- and OFF- type RGCs in sections from normal retinas and from retinas that had been subjected to glaucoma for 4 weeks.ResultsQuercetin can reverse the decrease in PhNR amplitude caused by chronic glaucoma. The baseline frequency of miniature GABAergic inhibitory postsynaptic currents (mIPSCs) in the RGCs of glaucomatous retinal slices was lower than that of the control group. The frequencies of miniature excitatory postsynaptic currents (mEPSCs) were not significantly different between control and glaucomatous RGCs. The baseline frequencies of GABAergic mIPSCs and mEPSCs in OFF-type glaucomatous RGCs were greater than those in ON-type glaucomatous RGCs. Quercetin increased miniature GABAergic inhibitory neurotransmission to RGCs and decreased miniature glutamatergic excitatory neurotransmission, reducing the excitability of the RGCs themselves, thus alleviating the excitability of RGCs in glaucomatous slices.ConclusionQuercetin may be a promising therapeutic agent for improving RGC survival and function in glaucomatous neurodegeneration. Quercetin exerted direct protective effects on RGCs by increasing inhibitory neurotransmission and decreasing excitatory neurotransmission to RGCs, thus reducing excitotoxic damage to those cells in glaucoma.

Olfactory proteotyping: towards the enlightenment of the neurodegeneration.

Olfactory proteotyping: towards the enlightenment of the neurodegeneration.

Announcing the first novel class of rapid-onset antidepressants in clinical practice

This study was designed with the rational aim/purpose of announcing and discussing the new class of rapid-onset antidepressants that will bring forth significant improvement and positive impact to the management of patients with depression disorders in clinical practice. The class of N-methyl-D-aspartate-glutamatergic ionoceptor blockers represent the first separate novel class of rapid-onset antidepressants with a direct action on the excitatory glutamatergic neurotransmission system but no direct action on the serotonergic, noradrenergic, or dopaminergic neurotransmission systems. It consistently fits into the antidepressants' classification nomenclature, and the pharmacological properties also deemed it appropriate to be accepted and announced as the first separate novel class of rapid-onset antidepressants.

Cyclisation of Cell-Penetrating PDZ-Binding Peptides Directed to PSD95

Excitatory glutamatergic neurotransmission via N-methyl-D-aspartate receptor (NMDAR) is critical for synaptic plasticity and survival of neurons. Excessive NMDAR activity, however can cause excitotoxicity and promote cell death, underlying a potential mechanism of neurodegeneration occurring in Alzheimer’s disease (AD). The regulation of calcium levels at synapses is important for pre- and post-synaptic activation in the hippocampus, where glutamate is the primary neurotransmitter, acting via metabotropic and ionotropic receptors.

Central adenosine A1 receptors inhibit cough via suppression of excitatory glutamatergic and tachykininergic neurotransmission.

The adenosine A1 receptor is reported to mediate several excitatory effects in the airways and has inhibitory effects in the CNS. In this study, we investigated the role of peripheral and central A1 receptors in regulating cough and airway obstruction. Drugs were administered to guinea pigs via inhalation or i.c.v. infusion. Following the administration of different drugs, cough was induced by exposing guinea pigs to aerosolized 0.4M citric acid. An automated analyser recorded both cough and airway obstruction simultaneously using whole-body plethysmography. The A1 receptor agonist, cyclopentyladenosine (CPA, administered by inhalation), dose-dependently inhibited cough and also inhibited airway obstruction. Similarly, CPA, administered i.c.v., inhibited both the citric acid-induced cough and airway obstruction; this was prevented by pretreatment with the A1 receptor antagonist DPCPX (i.c.v.). Treatment with DPCPX alone dose-dependently enhanced the citric acid-induced cough and airway obstruction. This effect was reversed following treatment with either the glutamate GluN1 receptor antagonist D-AP5 or the neurokinin NK1 receptor antagonist FK-888. These findings suggest that activation of either peripheral or central adenosine A1 receptors inhibits citric acid-induced cough and airway obstruction. The data also suggest that tonic activation of central adenosine A1 receptors serves as a negative regulator of cough and airway obstruction, secondary to inhibition of excitatory glutamatergic and tachykininergic neurotransmission.