Neurotransmitter Glutamate Research Articles

GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases.

N-methyl-D-aspartate receptors (NMDARs) are ion channels that respond to the neurotransmitter glutamate, playing a crucial role in the permeability of calcium ions and excitatory neurotransmission in the central nervous system (CNS). Composed of various subunits, NMDARs are predominantly formed by two obligatory GluN1 subunits (with eight splice variants) along with regulatory subunits GluN2 (GluN2A-2D) and GluN3 (GluN3A-B). They are widely distributed throughout the CNS and are involved in essential functions such as synaptic transmission, learning, memory, plasticity, and excitotoxicity. The presence of GluN2A and GluN2B subunits is particularly important for cognitive processes and has been strongly implicated in neurodegenerative diseases like Parkinson's disease and Alzheimer's disease. Understanding the roles of GluN2A and GluN2B NMDARs in neuropathologies provides valuable insights into the underlying causes and complexities of major nervous system disorders. This knowledge is vital for the development of selective antagonists targeting GluN2A and GluN2B subunits using pharmacological and molecular methods. Such antagonists represent a promising class of NMDA receptor inhibitors that have the potential to be developed into neuroprotective drugs with optimal therapeutic profiles.

Amelioration of rotenone-induced Parkinson's disease; comparing therapeutic role of erythropoietin versus low-level laser activation of mesenchymal stem cells (an in-vivo and in-vitro study)

ABSTRACT Parkinson's disease (PD), the second common neurodegenerative disease, is characterized by the loss of the dopaminergic neurons in the substantia nigra (SN). Because of L-dopa's side effects, new therapeutic methods were considered such as stem cells for PD treatment. The major challenge facing stem cell therapy following transplantations is their peripheral sequestration and decreased survival. Thus, the ability of erythropoietin (EPO) and low-level laser therapy (LLLT) to enhance mesenchymal stem cell (MSC) proliferation and therapeutic efficiency for alleviating rotenone-induced PD was investigated. Therefore, we compared the influence of stem cell preconditioning with erythropoietin versus LLLT on MSCs’ homing ability and the chances of survival. Forty-eight male Swiss mice were included in the in vivo protocol and ten in the in vitro work. The mice in the in vivo study were divided randomly into six groups (8 in each); group I; control group and group II; induced PD (untreated) group, group III; L-dopa, group IV; MSCs, group V; EPO-activated MSCs and group VI; laser-activated MSCs. Treatment with MSCs (either preconditioned or not) improved these neurological features by restoring the normal balance between glutamate and GABA neurotransmitters, and dopamine as well as increased tyrosine hydroxylase levels. Stem cell therapy decreased oxidative stress, miRNA-155 levels, enhanced neuronal architecture in SN, and decreased the number of apoptotic cells. LLLT enhanced MSC expression of integrin β1 which was reflected in the homing of PKH26-labelled MSCs into corpus striatum and SN. Thus, the optimum results were achieved with laser-activated MSCs.

Effects of Chronic Hydrocodone Exposure and Ceftriaxone on the Expression of Astrocytic Glutamate Transporters in Mesocorticolimbic Brain Regions of C57/BL Mice.

Exposure to opioids can lead to the alteration of several neurotransmitters. Among these neurotransmitters, glutamate is thought to be involved in opioid dependence. Glutamate neurotransmission is mainly regulated by astrocytic glutamate transporters such as glutamate transporter 1 (GLT-1) and cystine/glutamate antiporter (xCT). Our laboratory has shown that exposure to lower doses of hydrocodone reduced the expression of xCT in the nucleus accumbens (NAc) and the hippocampus. In the present study, we investigated the effects of chronic exposure to hydrocodone, and tested ceftriaxone as a GLT-1 upregulator in mesocorticolimbic brain regions such as the NAc, the amygdala (AMY), and the dorsomedial prefrontal cortex (dmPFC). Eight-week-old male mice were divided into three groups: (1) the saline vehicle control group; (2) the hydrocodone group; and (3) the hydrocodone + ceftriaxone group. Mice were injected with hydrocodone (10 mg/kg, i.p.) or saline for 14 days. On day seven, the hydrocodone/ceftriaxone group was injected with ceftriaxone (200 mg/kg, i.p.) for last seven days. Chronic exposure to hydrocodone reduced the expression of GLT-1, xCT, protein kinase B (AKT), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal Kinase (JNK) in NAc, AMY, and dmPFC. However, hydrocodone exposure increased the expression of G-protein-coupled metabotropic glutamate receptors (mGluR5) in the NAc, AMY, and dmPFC. Importantly, ceftriaxone treatment normalized the expression of mGluR5, GLT-1, and xCT in all these brain regions, except for xCT in the AMY. Importantly, ceftriaxone treatment attenuated hydrocodone-induced downregulation of signaling pathways such as AKT, ERK, and JNK expression in the NAc, AMY, and dmPFC. These findings demonstrate that ceftriaxone has potential therapeutic effects in reversing hydrocodone-induced downregulation of GLT-1 and xCT in selected reward brain regions, and this might be mediated through the downstream kinase signaling pathways such as AKT, ERK, and JNK.

Environmentally persistent free radicals on photoaged nanopolystyrene induce neurotoxicity by affecting dopamine, glutamate, serotonin and GABA in Caenorhabditis elegans

Microplastics are widely detected in the environment and induce toxic effects in various organisms. However, the properties and toxicity associated with environmentally persistent free radicals (EPFRs) in photoaged nanopolystyrene (NPS) remain largely unknown. We investigated the generation of EPFRs on photoaged NPS and their neurotoxicity and underlying mechanism in Caenorhabditis elegans. The results suggested that photoaging induces the generation of EPFRs and reactive oxygen species (O2•−, •OH, and 1O2), which altered the physicochemical properties (morphology, crystallinity, and functional groups) of NPS. Acute exposure to 1 μg/L of NPS-60 (NPS with light irradiation time of 60 d) significantly decreased locomotion behaviors and neurotransmitter contents (e.g., glutamate, serotonin, dopamine, and γ-aminobutyric acid). Treatment with N-acetyl-L-cysteine (NAC) by radical quenching test significantly reduced EPFRs levels on the aged NPS, and the toxicity of NAC-quenching NPS was decreased in nematodes compared to those in photoaged NPS. EPFRs also caused dysfunction of neurotransmission-related gene expression in C. elegans. Thus, EPFRs generated on photoaged NPS contributed to neurotoxicity by affecting dopamine, glutamate, serotonin, and γ-aminobutyric acid neurotransmission. The study highlights the potential risks of photoaged NPS and the contributions of EPFRs to toxicity.

Novel substituted 4-(Arylethynyl)-Pyrrolo[2,3-d]pyrimidines negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu5) Treat depressive disorder in mice

In view of the fact that the G-protein-coupled receptors (GPCRs) sit at the top of the signaling pathways triggering a diverse range of signaling cascades towards a cellular event, GPCRs are regarded as central drug targets. mGlu5, a type of classical GPCRs, is highly expressed in the central nervous system (CNS) and responds to the neurotransmitter glutamate. Researches show that mGlu5 is a potential drug target for the treatment of depression. Up to now, multiple mGlu5 negative allosteric modulators (NAMs) have entered clinical trials, but no small molecule mGlu5 NAM has yet to reach market. Herein, we report the structural optimization and structure-activity relationship studies of a series of novel mGlu5 NAMs. Among them, the novel compound 10b is a high-affinity mGluR5 antagonist, with an IC50 value of 11.5 nM. Besides, we evaluated the anti-depressant effect of compound 10b using the chronic unpredictable mild stress (CUMS)-induced depression model. The data showed that the mice in CUMS group were featured by decreased level of serum 5-HT and increased level of serum CORT, and the expression of synaptic proteins were reduced, including GluA1, GluA2, p-PKA, BDNF and TrkB. However, those factors for identifying sensitivity to depression-like behaviors could be improved by compound 10b treatment. The preliminary toxicology evaluations indicated that compound 10b had a good safety profile in vivo. Collectively, the compound 10b represents a promising lead compound for the treatment of depressive disorder.

Effects of isoflurane and urethane anesthetics on glutamate neurotransmission in rat brain using in vivo amperometry

BackgroundAspects of glutamate neurotransmission implicated in normal and pathological conditions are predominantly evaluated using in vivo recording paradigms in rats anesthetized with isoflurane or urethane. Urethane and isoflurane anesthesia influence glutamate neurotransmission through different mechanisms; however, real-time outcome measures of potassium chloride (KCl)-evoked glutamate overflow and glutamate clearance kinetics have not been compared within and between regions of the brain. In order to maintain rigor and reproducibility within the literature between the two most common methods of anesthetized in vivo recording of glutamate, we compared glutamate signaling as a function of anesthesia and brain region in the rat strain most used in neuroscience.MethodsIn the following experiments, in vivo amperometric recordings of KCl-evoked glutamate overflow and glutamate clearance kinetics (uptake rate and T80) in the cortex, hippocampus, and thalamus were performed using glutamate-selective microelectrode arrays (MEAs) in young adult male, Sprague-Dawley rats anesthetized with either isoflurane or urethane.ResultsPotassium chloride (KCl)-evoked glutamate overflow was similar under urethane and isoflurane anesthesia in all brain regions studied. Analysis of glutamate clearance determined that the uptake rate was significantly faster (53.2%, p < 0.05) within the thalamus under urethane compared to isoflurane, but no differences were measured in the cortex or hippocampus. Under urethane, glutamate clearance parameters were region-dependent, with significantly faster glutamate clearance in the thalamus compared to the cortex but not the hippocampus (p < 0.05). No region-dependent differences were measured for glutamate overflow using isoflurane.ConclusionsThese data support that amperometric recordings of KCl-evoked glutamate under isoflurane and urethane anesthesia result in similar and comparable data. However, certain parameters of glutamate clearance can vary based on choice of anesthesia and brain region. In these circumstances, special considerations are needed when comparing previous literature and planning future experiments.

EVALUATION OF THE POTENTIAL NEUROACTIVITY IN THE BRAIN NERVE TERMINALS OF THE C60 FULLERENE PLANETARY DUST COMPONENT

A study of the infrared spectrum of the environment of the planetary nebula Tc 1 revealed the radiation of cold and neutral fullerenes C60 and C70. The results of the analysis of infrared spectra obtained using the Hubble space telescope conclusively proved the existence of C60+ fullerene in the interstellar medium. These large carbon-containing molecules can form and exist in the interstellar medium and are candidates to explain many diffuse interstellar absorption bands. In this study, the potential neuroactivity of the C60 fullerene as a planetary dust component was assessed in the isolated rat brain nerve terminals. It was shown that C60 fullerene in the unirradiated state at concentrations of 0.05—0.25 mg/ml did not change the extracellular levels of excitatory neurotransmitter L-[ 14C]glutamate and inhibitory neurotransmitter [ 3H]GABA in the preparations of rat brain nerve terminals. An increase in fullerene C60 concentrations up to 0.5 and 1.00 mg/ml was accompanied by an increase in the extracellular levels of L-[ 14C]glutamate and [3 H]GABA in the preparations of nerve terminals. Therefore, fullerene C60 did not cause signs of acute neurotoxicity in the brain nerve terminals within the concentration range of 0.05—0.25 mg/ml. However, given that C60 undergoes photooxidation, it can be expected that it may acquire neurotoxic properties in situ.

Additional evidence supports GRM6 p.Thr178Met as a cause of congenital stationary night blindness in three horse breeds.

Congenital stationary night blindness (CSNB) is an ocular disorder characterized by nyctalopia. An autosomal recessive missense mutation in glutamate metabotropic receptor 6 (GRM6 c.533C>T, p.(Thr178Met)), called CSNB2, was previously identified in one Tennessee Walking Horse and predicted to reduce binding affinity of the neurotransmitter glutamate, impacting the retinal rod ON-bipolar cell signaling pathway. Thus, the first aim was to identify the allele frequency (AF) of CSNB2 in breeds with reported cases of CSNB and breeds closely related to the Tennessee Walking Horse. The second aim was to perform ocular examinations in multiple breeds to confirm the link between genotype and CSNB phenotype. In evaluating 3518 horses from 14 breeds, the CSNB2 allele was identified in nine previously unreported breeds. The estimated AF was highest in pacing Standardbreds (0.17) and lowest in American Quarter Horses (0.0010). Complete ophthalmic examinations and electroretinograms (ERG) were performed on 19 horses from three breeds, including one CSNB2 homozygote from each breed. All three CSNB2/CSNB2 horses had an electronegative ERG waveform under scotopic light conditions consistent with CSNB. The remaining 16 horses (seven CSNB2/N and nine N/N) had normal scotopic ERG results. All horses had normal photopic ERGs. This study provides additional evidence that GRM6 c.533C>T homozygosity is likely causal to CSNB in Tennessee Walking Horses, Standardbreds, and Missouri Fox Trotting Horses. Genetic testing is recommended for breeds with the CSNB2 allele to limit the production of affected horses. This study represents the largest across-breed identification of CSNB in the horse and suggests that this disorder is likely underdiagnosed.

UBR-1 ubiquitin ligase regulates the balance between GABAergic and glutamatergic signaling.

Excitation/inhibition (E/I) balance is carefully maintained by the nervous system. The neurotransmitter GABA has been reported to be co-released with its sole precursor, the neurotransmitter glutamate. The genetic and circuitry mechanisms to establish the balance between GABAergic and glutamatergic signaling have not been fully elucidated. Caenorhabditis elegans DVB is an excitatory GABAergic motoneuron that drives the expulsion step in the defecation motor program. We show here that in addition to UNC-47, the vesicular GABA transporter, DVB also expresses EAT-4, a vesicular glutamate transporter. UBR-1, a conserved ubiquitin ligase, regulates DVB activity by suppressing a bidirectional inhibitory glutamate signaling. Loss of UBR-1 impairs DVB Ca2+ activity and expulsion frequency. These impairments are fully compensated by the knockdown of EAT-4 in DVB. Further, glutamate-gated chloride channels GLC-3 and GLC-2/4 receive DVB's glutamate signals to inhibit DVB and enteric muscle activity, respectively. These results implicate an intrinsic cellular mechanism that promotes the inherent asymmetric neural activity. We propose that elevated glutamate in ubr-1 mutants, being the cause of the E/I shift, potentially contributes to Johanson Blizzard syndrome.

THU127 Deletion Of VGLUT2 In MCH Neurons Induces Sex-Specific Changes In Metabolic And Reproductive Function

Abstract Disclosure: B.G. Beekly: None. MCH neurons have a well-established role in metabolism and energy balance. MCH-knockout (“MCH-KO”) mice, which lack the MCH peptide itself, are hyperactive, hypophagic, and lean. However, MCH neurons express numerous genes involved in the synthesis, packaging, and release of the classical neurotransmitters GABA and glutamate, which are the central nervous system’s predominant inhibitory and excitatory neurotransmitters, respectively. These genes are also critical for normal metabolism, as the conditional deletion of glutamatergic signaling from MCH neurons also affects energy balance in ways that both mirror and differ from MCH-KO. When the metabolic phenotypes of MCH neuronal ablation (diphtheria toxin), MCH-KO, and transgenic Pmch-Cre;Slc17a6fl/fl mice (which lack VGLUT2 in MCH neurons) are compared, all three experimental groups exhibit decreased body weight and adiposity, increased locomotor activity, late-onset hypophagia, attenuated weight gain on high-fat diet, and reductions in circulating leptin. These data point to some functional redundancy between MCH and glutamate release from MCH neurons in the context of energy balance. By contrast, specific indicators of glucose sensing and handling differ between groups: MCH neuronal ablation and conditional VGLUT2 deletion in MCH neurons, but not global MCH-KO, result in reduced sucrose preference and improved glucose tolerance. These data suggest a role for MCH peptide in body weight regulation, but also a glutamate-dependent mechanism by which MCH neurons contribute to glucose homeostasis. Given the findings related to MCH peptide action on pancreatic islet cells and its effects on insulin resistance, it appears that MCH and glutamatergic signaling from MCH neurons must work synergistically for optimal regulation of energy balance. Importantly, all research to date on the metabolic effect of VGLUT2 deletion from MCH neurons has been in male mice. This constitutes a significant gap in the field’s understanding of these phenomena, particularly because of documented sex differences in glucose handling and associated metabolic disorders like diabetes. To address these gap, we generated Pmch-Cre;Slc17a6fl/fl mice, which lack functional VGLUT2 in MCH neurons. Body weight was measured from weaning until 20 weeks of age and the mice were subjected to comprehensive metabolic testing including oral glucose tolerance testing. We were able to recapitulate some, but not all, of the published findings in males, a fact which may in large part be due to strain differences in metabolism and glucose handling. Notably, several sexually dimorphic phenotypes were also observed, reaffirming the importance of incorporating biological sex variables into metabolic studies. Presentation: Thursday, June 15, 2023

GHRH Neurons from the Ventromedial Hypothalamic Nucleus Provide Dynamic and Sex-Specific Input to the Brain Glucose-Regulatory Network.

The ventromedial hypothalamic nucleus (VMN) controls glucose counter-regulation, including pituitary growth hormone (GH) secretion. VMN neurons that express the transcription factor steroidogenic factor-1/NR5A1 (SF-1) participate in glucose homeostasis. Research utilized in vivo gene knockdown tools to determine if VMN growth hormone-releasing hormone (Ghrh) regulates hypoglycemic patterns of glucagon, corticosterone, and GH outflow according to sex. Intra-VMN Ghrh siRNA administration blunted hypoglycemic hypercorticosteronemia in each sex, but abolished elevated GH release in males only. Single-cell multiplex qPCR showed that dorsomedial VMN (VMNdm) Ghrh neurons express mRNAs encoding Ghrh, SF-1, and protein markers for glucose-inhibitory (γ-aminobutyric acid) or -stimulatory (nitric oxide; glutamate) neurotransmitters. Hypoglycemia decreased glutamate decarboxylase67 (GAD67) transcripts in male, not female VMNdm Ghrh/SF-1 neurons, a response that was refractory to Ghrh siRNA. Ghrh gene knockdown prevented, in each sex, hypoglycemic down-regulation of Ghrh/SF-1 nerve cell GAD65 transcription. Ghrh siRNA amplified hypoglycemia-associated up-regulation of Ghrh/SF-1 neuron nitric oxide synthase mRNA in male and female, without affecting glutaminase gene expression. Ghrh gene knockdown altered Ghrh/SF-1 neuron estrogen receptor-alpha (ERα) and ER-beta transcripts in hypoglycemic male, not female rats, but up-regulated GPR81 lactate receptor mRNA in both sexes. Outcomes infer that VMNdm Ghrh/SF-1 neurons may be an effector of SF-1 control of counter-regulation, and document Ghrh modulation of hypoglycemic patterns of glucose-regulatory neurotransmitter along with estradiol and lactate receptor gene transcription in these cells. Co-transmission of glucose-inhibitory and -stimulatory neurochemicals of diverse chemical structure, spatial, and temporal profiles may enable VMNdm Ghrh neurons to provide complex dynamic, sex-specific input to the brain glucose-regulatory network.

Treatment resistance NMDA receptor pathway polygenic score is associated with brain glutamate in schizophrenia.

Dysfunction of glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia and may be particularly relevant in severe, treatment-resistant symptoms. The underlying mechanism may involve hypofunction of the NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed of genetic variants within NMDA receptor encoding genes, are associated with cortical glutamate in schizophrenia. Anterior cingulate cortex (ACC) glutamate was measured in 70 participants across 4 research sites using Proton Magnetic Resonance Spectroscopy (1H-MRS). Two NMDA receptor gene sets were sourced from the Molecular Signatories Database and NMDA receptor pathway polygenic scores were constructed using PRSet. The NMDA receptor pathway polygenic scores were weighted by single nucleotide polymorphism (SNP) associations with treatment-resistant schizophrenia, and associations with ACC glutamate were tested. We then tested whether NMDA receptor pathway polygenic scores with SNPs weighted by associations with non-treatment-resistant schizophrenia were associated with ACC glutamate. A higher NMDA receptor complex pathway polygenic score was significantly associated with lower ACC glutamate (β=-0.25, 95% CI=-0.49, -0.02, competitive p=0.03). When SNPs were weighted by associations with non-treatment-resistant schizophrenia, there was no association between the NMDA receptor complex pathway polygenic score and ACC glutamate (β=0.05, 95% CI=-0.18, 0.27, competitive p=0.79). These results provide initial evidence of an association between common genetic variation implicated in NMDA receptor function and ACC glutamate levels in schizophrenia. This association was specific to when the NMDA receptor complex pathway polygenic score was weighted by SNP associations with treatment-resistant schizophrenia.

HDAC-Mediated Glial Crosstalk Mediates Radiation Induced Memory Changes from Whole Brain Radiation in a Mouse Model

Prior work demonstrated radiation sensitivity can be regulated via Class III HDAC-mediated intracellular DNA damage response coordinated with Wnt-beta catenin signaling. We hypothesized that radiation induced functional alterations in HDAC mediated glial crosstalk in the CNS produce intercellular signaling alterations leading to phenotypic changes in cognition following whole brain radiation exposure. Primary human astrocytes, human astrocytoma (U251), and immortalized human microglia (HMC3) were examined in vitro in response to treatment with conditioned media isolated from irradiated glial cells. Prior to treatment with either single-dose or fractionated radiation schedules, cells were transfected with siRNA expression vector for Sirt2, a class III HDAC, versus scrambled controls. Quantitative PCR and immunoblots for neurotransmitters, metabolism, and inflammatory markers were obtained. Cells exposed to conditioned media were examined by immunofluorescence for cytoskeletal alterations and changes in junctional proteins. The findings were correlated with in vivo qPCR and immunohistochemical changes in brain tissue and functional memory changes in Sirt2 knockout versus wild type mice after whole brain radiation using novel object recognition testing at 2 weeks and 6 month post radiation timepoints. Statistical analysis was performed using paired Students T test between treated and control groups. Cells treated with conditioned media produced from irradiated U251, astrocytes and microglia produced increased expression of inflammatory cytokines IL-6, IL-8, GM-CSF and VEGF. However, immunofluorescence of cells treated with conditioned media from irradiated Sirt2 knockdown microglia and primary astrocytes demonstrated qualitative disruptions in glutamate neurotransmitter metabolism and actin cytoskeletal alterations with changes in pseudopodia and lamellipodia after staining with phalloidin and neurofilament L, suggesting altered intercellular communication. Connexin 43 in gap junctions was increased >2-fold (p<0.05) after exposure to conditioned media, whereas E-cadherin in adherens junctions was not significantly affected. Novel object recognition testing of Sirt2 knockout mice demonstrated resistance to radiation induced memory decline from whole brain radiation at pre radiation day 5 versus post radiation days 5 and 185 compared to controls (p<0.05). Glial crosstalk can be mediated via elimination of a Class III HDAC and appears to be a key mediator of radiation induced disruptions of intercellular communication in the CNS, connecting radiation to structural changes on the cell surface to synaptic activity and neurotransmitter metabolism, leading to functional disputations in recognition memory similar to what is experienced by patients receiving brain radiotherapy. These data suggest glial cross talk as a new therapeutic avenue to combat radiation induced cognitive dysfunction.

Neonatal Maternal Separation Induces Sexual Dimorphism in Brain Development: The Influence on Amino Acid Levels and Cognitive Disorders.

Repeated maternal separation (MS) is a useful experimental model in rodents for studying the long-term influence of early-life stress on brain neurophysiology. In our work, we assessed the effect of repeated MS (postnatal day (PND)1-21, 180 min/day) on the postnatal development of rat brain regions involved in memory using proton magnetic resonance spectroscopy (1HMRS) for tissue volume and the level of amino acids such as glutamate, aspartate, glutamine, glycine and gamma-aminobutyric acid (GABA) in the hippocampus. We assessed whether these effects are sex dependent. We also use novel object recognition (NOR) task to examine the effect of MS on memory and the effect of ethanol on it. Finally, we attempted to ameliorate postnatal stress-induced memory deficits by using VU-29, a positive allosteric modulator (PAM) of the metabotropic glutamate type 5 (mGlu5) receptor. In males, we noted deficits in the levels of glutamate, glycine and glutamine and increases in GABA in the hippocampus. In addition, the values of perirhinal cortex, prefrontal cortex and insular cortex and CA3 were decreased in these animals. MS females, in contrast, demonstrated significant increase in glutamate levels and decrease in GABA levels in the hippocampus. Here, the CA1 values alone were increased. VU-29 administration ameliorated these cognitive deficits. Thus, MS stress disturbs amino acids levels mainly in the hippocampus of adult male rats, and enhancement of glutamate neurotransmission reversed recognition memory deficits in these animals.

Evaluation of prenatal administration of valproic acid on the cerebellum of albino rat offspring

Introduction: Autism is a severe neurodevelopmental disorder of poorly understood etiology; which may be genetic, epigenetic or environmental. Valproic acid (VPA), the most widely used antiepileptic drug, has been reported to increase the risk of autism among the offspring of human mothers who are medicated with it during early pregnancy. Aim: The current work aimed to study the biochemical and histological changes in the cerebellum of the offspring of prenatally VPA treated rats. Materials and Methods: Twelve pregnant female albino rats were divided into two groups; control and VPA treated (50 mg/kg/day orally). The cerebellar sections of male offspring rats were subjected to biochemical tests (brain tissue Malondialdehyde (MDA), Superoxide dismutase (SOD), Tumor necrosis factor-alpha (TNF-α) and glutamate), histological examination, immunohistochemical analyses for the expression of glial fibrillary acidic protein (GFAP) and Bcl-2 associated X protein (Bax), and electro microscopical studies. Results: VPA caused significant elevation in the brain levels of oxidative stress marker MDA, proinflammatory cytokine TNF-α and excitatory neurotransmitter glutamate, with significant reduction in the level of brain antioxidant marker SOD, compared to the control group.

From Mechanisms to Implications: Understanding the Molecular Neurotoxicity of Titanium Dioxide Nanoparticles.

Titanium dioxide nanoparticles (TiO2NPs) are widely produced and used nanoparticles. Yet, TiO2NP exposure may possess toxic effects to different cells and tissues, including the brain. Recent studies significantly expanded the understanding of the molecular mechanisms underlying TiO2NP neurotoxicity implicating a number of both direct and indirect mechanisms. In view of the significant recent progress in research on TiO2NP neurotoxicity, the objective of the present study is to provide a narrative review on the molecular mechanisms involved in its neurotoxicity, with a special focus on the studies published in the last decade. The existing data demosntrate that although TiO2NP may cross blood-brain barrier and accumulate in brain, its neurotoxic effects may be mediated by systemic toxicity. In addition to neuronal damage and impaired neurogenesis, TiO2NP exposure also results in reduced neurite outgrowth and impaired neurotransmitter metabolism, especially dopamine and glutamate. TiO2NP exposure was also shown to promote α-synuclein and β-amyloid aggregation, thus increasing its toxicity. Recent findings also suggest that epigenetic effects and alterations in gut microbiota biodiversity contribute to TiO2NP neurotoxicity. Correspondingly, in vivo studies demosntrated that TiO2NPs induce a wide spectrum of adverse neurobehavioral effects, while epidemiological data are lacking. In addition, TiO2NPs were shown to promote neurotoxic effects of other toxic compounds. Here we show the contribution of a wide spectrum of molecular mechanisms to TiO2NP-induced neurotoxicity; yet, the role of TiO2NP exposure in adverse neurological outcomes in humans has yet to be fully appreciated.

Analysis of the brain transcriptome for substance-associated genes: An update on large-scale genome-wide association studies.

Substance use disorder (SUD) arises from the initiation to subsequent regular, irregular and harmful use of substances such as alcohol, tobacco/nicotine and cannabis. While thousands of genetic variants have been identified from recent large-scale genome-wide association studies (GWAS), understanding their functions in substance involvement and investigating the mechanisms by which they act in the addiction circuits remains challenging. In this study, we re-analysed the brain regional transcriptome data from the most comprehensive postmortem transcriptomic study, with a focus on up- or down-regulation of substance-associated protein-coding genes in the addiction circuit-related brain regions (AddictRegions), including six cortical and 11 subcortical regions. We found that substance-associated genes were overrepresented in AddictRegions. Interestingly, we observed a greater degree of genetic overlap between initiation and use and between use and SUD than between initiation and SUD. Moreover, substance initiation, use and SUD-associated genes tend to shift their enriched AddictRegions from the cortical for initiation and, to a lesser extent, substance use to subcortical regions for SUD (e.g., thalamus, substantia nigra and ventral tegmental area). We also uncovered a pattern of coordinated cortical up-regulation and subcortical down-regulation for the genes associated with tobacco initiation and alcohol use. Moreover, the Gene Ontology terms of glutamate receptor activity and neurotransmitter binding were most significantly overrepresented in AddictRegion-upregulated, substance-associated genes, with the strongest enrichment for those involved in common substance use behaviours. Overall, our analysis provides a resource of AddictRegion-related transcriptomes for studying substance-associated genes and generates intriguing insights into the genetic control of substance initiation, use and SUD.

Action of Botulinum Neurotoxin E Type in Experimental Epilepsies.

Botulinum neurotoxins (BoNTs) are zinc endopeptidases produced by the Clostridium genus of anerobic bacteria, largely known for their ability to cleave synaptic proteins, leading to neuromuscular paralysis. In the central nervous system, BoNTs are known to block the release of glutamate neurotransmitter, and for this reason, researchers explored the possible therapeutic action in disorders characterized by neuronal hyperactivity, such as epilepsy. Thus, using multidisciplinary approaches and models of experimental epilepsy, we investigated the pharmacological potential of BoNT/E serotype. In this review, written in memory of Prof. Matteo Caleo, a pioneer in these studies, we go back over the hypotheses and experimental approaches that led us to the conclusion that intrahippocampal administration of BoNT/E (i) displays anticonvulsant effects if prophylactically delivered in a model of acute generalized seizures; (ii) does not have any antiepileptogenic action after the induction of status epilepticus; (iii) reduces frequency of spontaneous seizures in a model of recurrent seizures if delivered during the chronic phase but in a transient manner. Indeed, the control on spontaneous seizures stops when BoNT/E effects are off (few days), thus limiting its pharmacological potential in humans.

GABA and Glutamate in hMT+ Link to Individual Differences in Residual Visual Function After Occipital Stroke.

Damage to the primary visual cortex following an occipital stroke causes loss of conscious vision in the contralateral hemifield. Yet, some patients retain the ability to detect moving visual stimuli within their blind field. The present study asked whether such individual differences in blind field perception following loss of primary visual cortex could be explained by the concentration of neurotransmitters γ-aminobutyric acid (GABA) and glutamate or activity of the visual motion processing, human middle temporal complex (hMT+). We used magnetic resonance imaging in 19 patients with chronic occipital stroke to measure the concentration of neurotransmitters GABA and glutamate (proton magnetic resonance spectroscopy) and functional activity in hMT+ (functional magnetic resonance imaging). We also tested each participant on a 2-interval forced choice detection task using high-contrast, moving Gabor patches. We then measured and assessed the strength of relationships between participants' residual vision in their blind field and in vivo neurotransmitter concentrations, as well as visually evoked functional magnetic resonance imaging activity in their hMT+. Levels of GABA and glutamate were also measured in a sensorimotor region, which served as a control. Magnetic resonance spectroscopy-derived GABA and glutamate concentrations in hMT+ (but not sensorimotor cortex) strongly predicted blind-field visual detection abilities. Performance was inversely related to levels of both inhibitory and excitatory neurotransmitters in hMT+ but, surprisingly, did not correlate with visually evoked blood oxygenation level-dependent signal change in this motion-sensitive region. Levels of GABA and glutamate in hMT+ appear to provide superior information about motion detection capabilities inside perimetrically defined blind fields compared to blood oxygenation level-dependent signal changes-in essence, serving as biomarkers for the quality of residual visual processing in the blind-field. Whether they also reflect a potential for successful rehabilitation of visual function remains to be determined.

Under the umbrella of depression and Alzheimer's disease physiopathology: Can cannabinoids be a dual-pleiotropic therapy?

Depression and Alzheimer´s disease (AD) are two disorders highly prevalent worldwide. Depression affects more than 300 million people worldwide while AD affects 60-80% of the 55 million cases of dementia. Both diseases are affected by aging with high prevalence in elderly and share not only the main brain affected areas but also several physiopathological mechanisms. Depression disease is already ascribed as a risk factor to the development of AD. Despite the wide diversity of pharmacological treatments currently available in clinical practice for depression management, they remain associated to a slow recovery process and to treatment-resistant depression. On the other hand, AD treatment is essentially based in symptomatology relieve. Thus, the need for new multi-target treatments arises. Herein, we discuss the current state-of-art regarding the contribution of the endocannabinoid system (ECS) in synaptic transmission processes, synapses plasticity and neurogenesis and consequently the use of exogenous cannabinoids in the treatment of depression and on delaying the progression of AD. Besides the well-known imbalance of neurotransmitter levels, including serotonin, noradrenaline, dopamine and glutamate, recent scientific evidence highlights aberrant spine density, neuroinflammation, dysregulation of neurotrophic factor levels and formation of amyloid beta (Aβ) peptides, as the main physiopathological mechanisms compromised in depression and AD. The contribution of the ECS in these mechanisms is herein specified as well as the pleiotropic effects of phytocannabinoids. At the end, it became evident that Cannabinol, Cannabidiol, Cannabigerol, Cannabidivarin and Cannabichromene may act in novel therapeutic targets, presenting high potential in the pharmacotherapy of both diseases.