Action Of Glutamate Research Articles

Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons.

A unique population of ventral tegmental area (VTA) neurons co-transmits glutamate and GABA. However, the circuit inputs to VTA VGluT2+VGaT+ neurons are unknown, limiting our understanding of their functional capabilities. By coupling monosynaptic rabies tracing with intersectional genetic targeting in male and female mice, we found that VTA VGluT2+VGaT+ neurons received diverse brain-wide inputs. The largest numbers of monosynaptic inputs to VTA VGluT2+VGaT+ neurons were from superior colliculus, lateral hypothalamus, midbrain reticular nucleus, and periaqueductal gray, whereas the densest inputs relative to brain region volume were from dorsal raphe nucleus, lateral habenula, and ventral tegmental area. Based on these and prior data, we hypothesized that lateral hypothalamus and superior colliculus inputs were glutamatergic neurons. Optical activation of glutamatergic lateral hypothalamus neurons activated VTA VGluT2+VGaT+ neurons regardless of stimulation frequency and resulted in flee-like ambulatory behavior. In contrast, optical activation of glutamatergic superior colliculus neurons activated VTA VGluT2+VGaT+ neurons for a brief period of time at high stimulation frequency and resulted in head rotation and arrested ambulatory behavior (freezing). Stimulation of glutamatergic lateral hypothalamus neurons, but not glutamatergic superior colliculus neurons, was associated with VTA VGluT2+VGaT+ footshock-induced activity. In addition, inhibition of lateral hypothalamus glutamatergic neurons disrupted VTA VGluT2+VGaT+ tailshock-induced activity. We interpret these results such that inputs to VTA VGluT2+VGaT+ neurons may integrate diverse signals related to the detection and processing of motivationally-salient outcomes.Significance Statement VTA glutamate neurons have roles in motivated behavior and unique neurotransmission capabilities. A specific VTA glutamate neuron subtype, those that co-transmit glutamate and GABA, have unique outcome signaling properties compared to other VTA cell-types. However, the circuits that regulate these neurons are unclear. We identified the whole-brain inputs to VTA glutamate and GABA co-transmitting neurons. We also identify two distinct glutamatergic inputs that activate VTA glutamate and GABA co-transmitting neurons and result in different behavioral repertoires suggestive of threat processing. Together, these results provide novel insights into the circuit and cell-type specific influences on VTA glutamate and GABA co-transmitting neuronal activity as integrators of motivationally salient outcomes.

Design, Optimization and Performance Assessment of Memantine Buccal Films for Targeted Drug Delivery.

Memantine is primarily prescribed for treating moderate to severe Alzheimer’s disease by modulating glutamate, a key neurotransmitter involved in cognitive functions like memory and learning. By blocking excessive glutamate activity at NMDA receptors, memantine helps improve cognitive function and slow symptom progression in Alzheimer’s patients. In this study, solvent evaporation was used in the formulation of memantine in order to increase its bioavailability and sustain its release. Chitosan, HPMC, a mucoadhesive polymer, carbopol, a sensitive to pH polymer and propyle glycol, a permeation enhancer, were all incorporated in the formulation. All formulations underwent evaluation for moisture content, folding endurance, swelling index, mucoadhesive strength and drug content. Drug release profiles were assessed through in-vitro diffusion studies. Results indicated that increasing concentrations of polymers led to higher mucoadhesive strength, consequently enhancing Memantine release from the system. The optimal formulation(F9), with carefully balanced polymer concentrations, demonstrated more resident time, sustained drug release and improved bioavailability.

Glutamate dynamics and BOLD response during OCD symptom provocation in the lateral occipital cortex: A 7 Tesla fMRI-fMRS study

Obsessive-compulsive disorder (OCD) is linked with dysfunction in frontal-striatal, fronto-limbic, and visual brain regions. Research using proton magnetic resonance spectroscopy (1H-MRS) suggests that altered neurometabolite levels, like glutamate, may contribute to this dysfunction. However, static neurometabolite levels in OCD patients have shown inconsistent results, likely due to previous studies' limited focus on neurometabolite dynamics. We employ functional MRS (fMRS) and functional magnetic resonance imaging (fMRI) to explore these dynamics and brain activation during OCD symptom provocation.We utilized a combined 7-tesla fMRI-fMRS setup to examine task-related BOLD response and glutamate changes in the lateral occipital cortex (LOC) of 30 OCD participants and 34 matched controls during an OCD-specific symptom provocation task. The study examined main effects and between-group differences in brain activation and glutamate levels during the task.A whole sample task-effects analysis on data meeting predefined quality criteria showed significant glutamate increases (n = 41 (22 OCD, 19 controls), mean change: 3.2 %, z = 3.75, p < .001) and task activation (n = 54 (26 OCD, 28 controls), p < .001) in the LOC during OCD blocks compared to neutral blocks. However, no differences in task-induced glutamate dynamics or activation between groups were found, nor a correlation between glutamate levels and task activation.We were able to measure task-induced increases in glutamate and BOLD levels, emphasizing its feasibility for OCD research. The absence of group differences highlights the need for further exploration to discern to what extent neurometabolite dynamics differ between OCD patients and controls. Once established, future studies can use pre-post intervention fMRS-fMRI to probe the effects of therapies modulating glutamate pathways in OCD.

Abstract P385: Effects Of a High Salt Diet On Glutamatergic Signaling In The Nucleus Of The Solitary Tract And Baroreflex Sensitivity

Hypertension remains a global health concern. Studies have shown a correlation with the loss of normal 24-hour blood pressure patterns and hypertension with a high salt diet. However, the mechanisms behind this are not fully known. The nucleus of the solitary tract (nTS), a key medullary nucleus involved in cardiorespiratory regulation, is known to modulate sympathetic outflow and blood pressure alterations.When blood pressure increases, baroreceptors in peripheral vessels detect these changes and send signals to the nTS through the neurotransmitter glutamate. Increased nTS glutamatergic signaling decreases blood pressure via efferent signals to the heart and blood vessels. The nTS integrates these signals and initiates responses through the baroreflex to counteract changes in blood pressure. Thus, baroreflex sensitivity (BRS), or a measure of how the baroreflex adjusts, serves as an indicator of the regulation of this feedback loop. An increased BRS indicates a more robust ability of the body to respond to blood pressure changes. Conversely, a reduced BRS is associated with hypertension, and autonomic dysfunction. Studies have shown that those with diet-induced hypertension also have a decreased BRS, however, the mechanism is not clear. We hypothesize that dysregulation of the 24-hour circadian glutamatergic signaling within the nTS may cause BRS decrease and hypertension. Salt-sensitive rats were subjected to either a normal salt diet (NSD, 0.4 % NaCl) or high salt diet (HSD, 4% NaCl) for 7 weeks. To determine nTS changes related to HSD, we measured blood pressure using 24/7 telemetry, and activation of glutamatergic neurons via immunohistochemistry (IHC). Antibodies against glutamate (CAMKII) and neuronal activation (cFos) were used to detect neuronal activation 6 hours apart, at the end of the NSD or HSD. Our preliminary findings reveal near significant decreases in glutamate signaling during the active period (at 9pm), suggesting a potential shift in the excitatory signaling in the nTS. Additionally, HSD over 7 weeks caused a significant increase in blood pressure and a decrease in BRS during the active period. Our preliminary data shows a connection between 24-hour regulation of glutamate within the nTS, diet-induced hypertension, and loss of BRS. This dysregulation in the blood pressure regulation underscores the importance of understanding the molecular mechanisms linking diet and development of disease.

Exploring the Role of Bergamot Polyphenols in Alleviating Morphine-Induced Hyperalgesia and Tolerance through Modulation of Mitochondrial SIRT3.

Morphine is an important pain reliever employed in pain management, its extended utilize is hindered by the onset of analgesic tolerance and oxidative stress. Long-term morphine administration causes elevated production of reactive oxygen species (ROS), disrupting mitochondrial function and inducing oxidation. Sirtuin 3 (SIRT3), a mitochondrial protein, is essential in modulating ROS levels by regulating mitochondrial antioxidant enzymes as manganese superoxide dismutase (MnSOD). Our investigation focused on the impact of SIRT3 on hyperalgesia and morphine tolerance in mice, as evaluating the antioxidant effect of the polyphenolic fraction of bergamot (BPF). Mice were administered morphine twice daily for four consecutive days (20 mg/kg). On the fifth day, mice received an acute dose of morphine (3 mg/kg), either alone or in conjunction with BPF or Mn (III)tetrakis (4-benzoic acid) porphyrin (MnTBAP). We evaluated levels of malondialdehyde (MDA), nitration, and the activity of SIRT3, MnSOD, glutamine synthetase (GS), and glutamate 1 transporter (GLT1) in the spinal cord. Our findings demonstrate that administering repeated doses of morphine led to the development of antinociceptive tolerance in mice, accompanied by increased superoxide production, nitration, and inactivation of mitochondrial SIRT3, MnSOD, GS, and GLT1. The combined administration of morphine with either BPF or MnTBAP prevented these effects.

Molecular mechanism of ligand gating and opening of NMDA receptor.

Glutamate transmission and activation of ionotropic glutamate receptors are the fundamental means by which neurons control their excitability and neuroplasticity1. The N-methyl-D-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands-glutamate and glycine-for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively2,3. The exact molecular mechanism for channel gating by the two ligands has been unclear, particularly without structures representing the open channel and apo states. Here we show that the channel gate opening requires tension in the linker connecting the LBD and transmembrane domain (TMD) and rotation of the extracellular domain relative to the TMD. Using electron cryomicroscopy, we captured the structure of theGluN1-GluN2B(GluN1-2B) NMDAR in its open state bound to a positive allosteric modulator. This process rotates and bends the pore-forming helices in GluN1 and GluN2B, altering the symmetry of the TMD channel from pseudofourfold to twofold. Structures of GluN1-2B NMDAR in apo and single-liganded states showed that binding of either glycine or glutamate alone leads to distinct GluN1-2B dimer arrangements but insufficient tension in the LBD-TMD linker for channel opening. This mechanistic framework identifies a key determinant for channel gating and a potential pharmacological strategy for modulating NMDAR activity.

Blockade of mGluR5 in nucleus accumbens modulates calcium sensor proteins, facilitates extinction, and attenuates reinstated morphine place preference in rats

Numerous findings confirm that the metabotropic glutamate receptors (mGluRs) are involved in the conditioned place preference (CPP) induced by morphine. Here we focused on the role of mGluR5 in the nucleus accumbens (NAc) as a main site of glutamate action on the rewarding effects of morphine. Firstly, we investigated the effects of intra-NAc administrating mGluR5 antagonist 3-((2-Methyl-1,3-thiazol-4-yl) ethynyl) pyridine hydrochloride (MTEP; 1, 3, and 10 μg/μl saline) on the extinction and the reinstatement phase of morphine CPP. Moreover, to determine the downstream signaling cascades of mGluR5 in morphine CPP, the protein levels of stromal interaction molecules (STIM1 and 2) in the NAc and hippocampus (HPC) were measured by western blotting. The behavioral data indicated that the mGluR5 blockade by MTEP at the high doses of 3 and 10 μg facilitated the extinction of morphine-induced CPP and attenuated the reinstatement to morphine in extinguished rats. Molecular results showed that the morphine led to increased levels of STIM proteins in the HPC and increased the level of STIM1 without affecting STIM2 in the NAc. Furthermore, intra-NAc microinjection of MTEP (10 μg) in the reinstatement phase decreased STIM1 in the NAc and HPC and reduced the STIM2 in the HPC. Collectively, our data show that morphine could facilitate brain reward function in part by increasing glutamate-mediated transmission through activation of mGluR5 and modulation of STIM proteins. Therefore, these results highlight the therapeutic potential of mGluR5 antagonists in morphine use disorder.

The Dopamine Hypothesis as a Causal Explanation of Schizophrenia

Schizophrenia, a severe psychiatric disorder, profoundly impacts individuals, families, and society, characterized by symptoms such as delusions, hallucinations, disorganized thinking, speech, and motor behavior, as outlined in the DSM-5 criteria. Coined by Eugen Bleuler in 1911 to emphasize fragmented cognition, the term "schizophrenia" replaced Emile Kraepelin's "dementia praecox"(1908) reflecting its chronic nature, with an estimated prevalence of 1% in the general population and a significant heritability rate of around 79%. The dopamine hypothesis, central to schizophrenia research, suggests heightened dopaminergic transmission as a primary factor in its development, supported by the efficacy of antipsychotic drugs targeting dopamine receptors. However, recent studies have revealed complexities beyond dopamine dysfunction, including the glutamate hypothesis, which proposes deficits in glutamate activity as an alternative explanation. This essay critically evaluates the dopamine hypothesis within the broader biopsychosocial framework, emphasizing the interaction of biological, psychological, and social factors in schizophrenia etiology. Despite its foundational role, the dopamine hypothesis has limitations in fully clarifying the multifaceted nature of schizophrenia, highlighting the need for comprehensive approaches integrating diverse perspectives and methodologies to enhance understanding of this complex disorder. Keywords: Dopamine Hypothesis, Schizophrenia, Mental Illness, Psychotic Symptoms, GENE x ENVIROMENT Interaction

γ-Oryzanol from Rice Bran Antagonizes Glutamate-Induced Excitotoxicity in an In Vitro Model of Differentiated HT-22 Cells.

The excessive activation of glutamate in the brain is a factor in the development of vascular dementia. γ-Oryzanol is a natural compound that has been shown to enhance brain function, but more research is needed to determine its potential as a treatment for vascular dementia. This study investigated if γ-oryzanol can delay or improve glutamate neurotoxicity in an in vitro model of differentiated HT-22 cells and explored its neuroprotective mechanisms. The differentiated HT-22 cells were treated with 0.1 mmol/L glutamate for 24 h then given γ-oryzanol at appropriate concentrations or memantine (10 µmol/L) for another 24 h. Glutamate produced reactive oxygen species and depleted glutathione in the cells, which reduced their viability. Mitochondrial dysfunction was also observed, including the inhibition of mitochondrial respiratory chain complex I activity, the collapse of mitochondrial transmembrane potential, and the reduction of intracellular ATP levels in the HT-22 cells. Calcium influx triggered by glutamate subsequently activated type II calcium/calmodulin-dependent protein kinase (CaMKII) in the HT-22 cells. The activation of CaMKII-ASK1-JNK MAP kinase cascade, decreased Bcl-2/Bax ratio, and increased Apaf-1-dependent caspase-9 activation were also observed due to glutamate induction, which were associated with increased DNA fragmentation. These events were attenuated when the cells were treated with γ-oryzanol (0.4 mmol/L) or the N-methyl-D-aspartate receptor antagonist memantine. The results suggest that γ-oryzanol has potent neuroprotective properties against glutamate excitotoxicity in differentiated HT-22 cells. Therefore, γ-oryzanol could be a promising candidate for the development of therapies for glutamate excitotoxicity-associated neurodegenerative diseases, including vascular dementia.

Maternal treatment with a selective delta-opioid receptor agonist during gestation has a sex-specific pro-cognitive action in offspring: mechanisms involved.

Background: There is growing evidence that the treatment of several mental disorders can potentially benefit from activation of delta-opioid receptors. In the future, delta-agonists with a safe pharmacological profile can be used for the treatment of mood disorders in pregnant women. However, the data on prenatal exposure to delta-opioid agonists are missing. The present study is aimed to test the hypothesis that the activation of delta-opioid receptors during gravidity has positive effects on the behaviour accompanied by changes in glutamate and monoamine neurotransmission. Methods: Gestating Wistar rats were chronically treated with a selective delta-agonist SNC80 or vehicle. Adult male and female offspring underwent novel object recognition (for the assessment of cognition) and open field (for the assessment of anxiety and habituation) tests, followed by in vivo electrophysiological examination of the activity of hippocampal glutamate and midbrain serotonin (5-HT) and dopamine neurons. Results: We found that the maternal treatment with SNC80 did not affect the offspring's anxiety, habituation, and 5-HT neuronal firing activity. Female offspring of SNC80-treated dams exhibited improved novelty recognition associated with decreased firing rate and burst activity of glutamate and dopamine neurons. Conclusion: Maternal treatment with delta-opioid agonists during gestation may have a pro-cognitive effect on offspring without any negative effects on anxiety and habituation. The putative pro-cognitive effect might be mediated via mechanism(s) involving the firing activity of hippocampal glutamate and mesolimbic dopamine neurons.

Functional Polyphenol-Based Nanoparticles Boosted the Neuroprotective Effect of Riluzole for Acute Spinal Cord Injury.

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.

On the functions of astrocyte-mediated neuronal slow inward currents.

Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extrasynaptic N-methyl-D-aspartate receptors with the contribution of astrocytes. These events are significantly slower than the excitatory postsynaptic currents. Parameters of slow inward currents are determined by several factors including the mechanisms of astrocytic activation and glutamate release, as well as the diffusion pathways from the release site towards the extrasynaptic receptors. Astrocytes are stimulated by neuronal network activity, which in turn excite neurons, forming an astrocyte-neuron feedback loop. Mostly as a consequence of brain edema, astrocytic swelling can also induce slow inward currents under pathological conditions. There is a growing body of evidence on the roles of slow inward currents on a single neuron or local network level. These events often occur in synchrony on neurons located in the same astrocytic domain. Besides synchronization of neuronal excitability, slow inward currents also set synaptic strength via eliciting timing-dependent synaptic plasticity. In addition, slow inward currents are also subject to non-synaptic plasticity triggered by long-lasting stimulation of the excitatory inputs. Of note, there might be important region-specific differences in the roles and actions triggering slow inward currents. In greater networks, the pathophysiological roles of slow inward currents can be better understood than physiological ones. Slow inward currents are identified in the pathophysiological background of autism, as slow inward currents drive early hypersynchrony of the neural networks. Slow inward currents are significant contributors to paroxysmal depolarizational shifts/interictal spikes. These events are related to epilepsy, but also found in Alzheimer's disease, Parkinson's disease, and stroke, leading to the decline of cognitive functions. Events with features overlapping with slow inward currents (excitatory, N-methyl-D-aspartate-receptor mediated currents with astrocytic contribution) as ischemic currents and spreading depolarization also have a well-known pathophysiological role in worsening consequences of stroke, traumatic brain injury, or epilepsy. One might assume that slow inward currents occurring with low frequency under physiological conditions might contribute to synaptic plasticity and memory formation. However, to state this, more experimental evidence from greater neuronal networks or the level of the individual is needed. In this review, I aimed to summarize findings on slow inward currents and to speculate on the potential functions of it.

Suppression of presynaptic corticostriatal glutamate activity attenuates L-dopa-induced dyskinesia in 6-OHDA-lesioned Parkinson's disease mice

A common adverse effect of Parkinson's disease (PD) treatment is L-dopa-induced dyskinesia (LID). This condition results from both dopamine (DA)-dependent and DA-independent mechanisms, as glutamate inputs from corticostriatal projection neurons impact DA-responsive medium spiny neurons in the striatum to cause the dyskinetic behaviors. In this study, we explored whether suppression of presynaptic corticostriatal glutamate inputs might affect the behavioral and biochemical outcomes associated with LID. We first established an animal model in which 6-hydroxydopamine (6-OHDA)-lesioned mice were treated daily with L-dopa (10 mg/kg, i.p.) for 2 weeks; these mice developed stereotypical abnormal involuntary movements (AIMs). When the mice were pretreated with the NMDA antagonist, amantadine, we observed suppression of AIMs and reductions of phosphorylated ERK1/2 and NR2B in the striatum. We then took an optogenetic approach to manipulate glutamatergic activity. Slc17a6 (vGluT2)-Cre mice were injected with pAAV5-Ef1a-DIO-eNpHR3.0-mCherry and received optic fiber implants in either the M1 motor cortex or dorsolateral striatum. Optogenetic inactivation at either optic fiber implant location could successfully reduce the intensity of AIMs after 6-OHDA lesioning and L-dopa treatment. Both optical manipulation strategies also suppressed phospho-ERK1/2 and phospho-NR2B signals in the striatum. Finally, we performed intrastriatal injections of LDN 212320 in the dyskenesic mice to enhance expression of glutamate uptake transporter GLT-1. Sixteen hours after the LDN 212320 treatment, L-dopa-induced AIMs were reduced along with the levels of striatal phospho-ERK1/2 and phospho-NR2B. Together, our results affirm a critical role of corticostriatal glutamate neurons in LID and strongly suggest that diminishing synaptic glutamate, either by suppression of neuronal activity or by upregulation of GLT-1, could be an effective approach for managing LID.

The role of the GABAergic system on insomnia.

Sleep is an essential activity for the survival of mammals. Good sleep quality helps promote the performance of daily functions. In contrast, insufficient sleep reduces the efficiency of daily activities, causes various chronic diseases like Alzheimer's disease, and increases the risk of having accidents. The GABAergic system is the primary inhibitory neurotransmitter system in the central nervous system. It transits the gamma-aminobutyric acid (GABA) neurotransmitter via GABAA and GABAB receptors to counterbalance excitatory neurotransmitters, such as glutamate, noradrenaline, serotonin, acetylcholine, orexin, and dopamine, which release and increase arousal activities during sleep. Several studies emphasized that dysfunction of the GABAergic system is related to insomnia, the most prevalent sleep-related disorder. The GABAergic system comprises the GABA neurotransmitter, GABA receptors, GABA synthesis, and degradation. Many studies have demonstrated that GABA levels correlate with sleep quality, suggesting that modulating the GABAergic system may be a promising therapeutic approach for insomnia. In this article, we highlight the significance of sleep, the classification and pathology of insomnia, and the impact of the GABAergic system changes on sleep. In addition, we also review the medications that target the GABAergic systems for insomnia, including benzodiazepines (BZDs), non-BZDs, barbiturates, GABA supplements, and Chinese herbal medicines.

Late onset psychosis treatment with adjunctive medicines.

A number of studies have shown the feasibility of using adjunctive drugs in late onset psychosis (LOP). Testing hypothesis that among LOP people treated with antipsychotics and antidepressants, basing on certain clinical characteristics a subgroup of patients might be distinguished, for whom adjunctive therapy is advantageous. This subgroup might be identified by measurement of blood biochemical parameters. 59 in-patients with LOP, treated neuroleptics and antidepressants, were included, and followed in real clinical practice. Database containing demographic, clinical data (scores by PANSS, CDSS, CGI-S, HAMD-17), prescribed therapy, adverse effects of antipsychotic and antidepressant treatment, and blood biochemical parameters (enzymatic activities of glutamate- and glutathione metabolism enzymes in platelets and erythrocytes) at baseline and after the treatment course was created. Three groups of patients (Gr1, Gr2, and Gr3), based on the adjunctive therapy usage were identified: Gr1 (n = 16) was without adjunctive therapy, two other groups (Gr2 and Gr3) were with adjunctive medicines, such as 2-ethyl-6-methyl-3-hydroxypyridine succinate (EMHS; Gr2, n = 20), or other drugs, such as citicoline, cerebrolysin, cortexin, actovegin, gliatilin (choline alfoscerate; Gr3, n = 23). The enzymatic activities were assessed also in the matched control group (n = 38). In all three patient groups, as compared with controls, activity of erythrocyte glutathione reductase was decreased at baseline and after the treatment course. In Gr2, unlike Gr1 or Gr3, there was a significant decrease in baseline glutamate dehydrogenase and glutathione-S-transferase activities. Certain clinical criteria were also elucidated for prescription of EMHS as adjunctive therapy for patients of Gr2. Glutamate dehydrogenase and glutathione-S-transferase activities returned closer to control levels after the treatment course in Gr2, unlike Gr1, where they declined yet more after psychotropic treatment without adjunctive medicine. Different significant links between biochemical parameters and scores by clinical scales were observed in Gr1, Gr2, and Gr3, some having predictive value for evaluation of antipsychotic treatment efficacy. We demonstrate the validity of adjunctive neuroprotective medicines' usage in addition to antipsychotic and antidepressant therapy in distinct subgroups of patients suffering with LOP, especially those who have prominent side effects accompanying their psychotropic treatment. Returning of biochemical parameters to control range following the treatment course observed in patients of the subgroup treated with adjunctive EMHS is evidence for their metabolism normalization.

The synergic effects of presynaptic calcium channel antagonists purified from spiders on memory elimination of glutamate-induced excitotoxicity in the rat hippocampus trisynaptic circuit

The hippocampus is a complex area of the mammalian brain and is responsible for learning and memory. The trisynaptic circuit engages with explicit memory. Hippocampal neurons express two types of presynaptic voltage-gated calcium channels (VGCCs) comprising N and P/Q-types. These VGCCs play a vital role in the release of neurotransmitters from presynaptic neurons. The chief excitatory neurotransmitter at these synapses is glutamate. Glutamate has an essential function in learning and memory under normal conditions. The release of neurotransmitters depends on the activity of presynaptic VGCCs. Excessive glutamate activity, due to either excessive release or insufficient uptake from the synapse, leads to a condition called excitotoxicity. This pathological state is common among all neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Under these conditions, glutamate adversely affects the trisynaptic circuitry, leading to synaptic destruction and loss of memory and learning performance. This study attempts to clarify the role of presynaptic VGCCs in memory performance and reveals that modulating the activity of presynaptic calcium channels in the trisynaptic pathway can regulate the excitotoxic state and consequently prevent the elimination of neurons and synaptic degradation. All of these can lead to an improvement in learning and memory function. In the current study, two calcium channel blockers—omega-agatoxin-Aa2a and omega-Lsp-IA—were extracted, purified, and identified from spiders (Agelena orientalis and Hogna radiata) and used to modulate N and P/Q VGCCs. The effect of omega-agatoxin-Aa2a and omega-Lsp-IA on glutamate-induced excitotoxicity in rats was evaluated using the Morris water maze task as a behavioral test. The local expression of synaptophysin (SYN) was visualized for synaptic quantification using an immunofluorescence assay. The electrophysiological amplitudes of the field excitatory postsynaptic potentials (fEPSPs) in the input-output and LTP curves of the mossy fiber and Schaffer collateral circuits were recorded. The results of our study demonstrated that N and P/Q VGCC modulation in the hippocampus trisynaptic circuit of rats with glutamate-induced excitotoxicity dysfunction could prevent the destructive consequences of excitotoxicity in synapses and improve memory function and performance.

Sex steroid hormones, the estrous cycle, and rapid modulation of glutamatergic synapse properties in the striatal brain regions with a focus on 17β-estradiol and the nucleus accumbens

The striatal brain regions encompassing the nucleus accumbens core (NAcc), shell (NAcs) and caudate-putamen (CPu) regulate cognitive functions including motivated behaviors, habit, learning, and sensorimotor action, among others. Sex steroid hormone sensitivity and sex differences have been documented in all of these functions in both normative and pathological contexts, including anxiety, depression and addiction. The neurotransmitter glutamate has been implicated in regulating these behaviors as well as striatal physiology, and there are likewise documented sex differences in glutamate action upon the striatal output neurons, the medium spiny neurons (MSNs). Here we review the available data regarding the role of steroid sex hormones such as 17β-estradiol (estradiol), progesterone, and testosterone in rapidly modulating MSN glutamatergic synapse properties, presented in the context of the estrous cycle as appropriate. Estradiol action upon glutamatergic synapse properties in female NAcc MSNs is most comprehensively discussed. In the female NAcc, MSNs exhibit development period-specific sex differences and estrous cycle variations in glutamatergic synapse properties as shown by multiple analyses, including that of miniature excitatory postsynaptic currents (mEPSCs). Estrous cycle-differences in NAcc MSN mEPSCs can be mimicked by acute exposure to estradiol or an ERα agonist. The available evidence, or lack thereof, is also discussed concerning estrogen action upon MSN glutamatergic synapse in the other striatal regions as well as the underexplored roles of progesterone and testosterone. We conclude that there is strong evidence regarding estradiol action upon glutamatergic synapse function in female NAcs MSNs and call for more research regarding other hormones and striatal regions.

Cross-talk between Peptide Neurotransmitters and their Role in Homeostasis of Brain, Behavior, and Immunity

Abstract: The bidirectional communication among the different peptide neurotransmitters and their receptors influences brain, immunity, and behavior. Among the peptide neurotransmitters, Glutamate is the primary excitatory while; gamma-aminobutyrate (γ-GABA), is the inhibitory neurotransmitter. Glutamatergic/GABAergic imbalances are seen in many neurological and autoimmune disorders. With an aim to understand more deeply the intricacies of glutamate/GABA homeostasis, we provide a critical review of glutamate, glycine and GABA peptide neurotransmitters and their role in the brain, behavior, and immunity. Another aspect of maintaining this homeostasis has its origin in the gut-brain-axis which influences mood and behavior via the bidirectional biochemical exchange network between central (CNS) and enteric nervous system (ENS). This present review also provides evidence of the cross-talk between glutamate, glycine, and GABA along the microbiotagut- brain axis, thus any variations in this axis bear the consequences of the pathological condition. Drugs like alcohol, Benzodiazepines (Barbiturates) and neurosteroids inhibit the excitatory action of glutamate leading to an overall increase of glutamate/GABA ratio that causes relaxation of nerves. However, these drugs are misused and abused among drug addicts and now their commercial production is either banned or downsized and heavily monitored. Because only a limited number of drug molecules are considered in pharmaceutics and clinics as antidepressants, it is essential to focus on alternate peptide modulator analogues which are safe, eco-friendly and can be used as drugs to relieve stress and anxiety. In this review, we present a synopsis of the studies on synthetic GABAergic agonists or GABA modulators that can be targeted for future therapeutics and clinics.

FRI275 Glutamate Receptor Agonists Stimulate Kisspeptin Neurons In The Arcuate Nucleus Of The Hypothalamus

Abstract Disclosure: R. Bearss: None. R. Piet: None. KNDy neurons co-express kisspeptin, neurokinin B (NKB), dynorphin A (Dyn A), and glutamate. These neurons, located in the arcuate nucleus of the hypothalamus, drive pulsatile gonadotropin releasing hormone (GnRH) secretion. This eventually promotes pulsatile gonadotropin hormone release from the anterior pituitary, important for fertility in both sexes. The current hypothesized mechanism for pulse generation involves KNDy neuron interconnectivity and reciprocal regulation through the combined actions of NKB, DynA and glutamate to coordinate KNDy neuron activity. There is evidence that KNDy neurons express NKB, Dyn A and glutamate receptors and that NKB stimulates KNDy neuron electrical activity while Dyn A suppresses it. There is also evidence that ionotropic glutamate receptor antagonists can inhibit KNDy neuron coordinated activity and pulsatile gonadotropin hormone release, indicating that glutamatergic neurotransmission plays a significant role in activity coordination. The purpose of the following experiments was to investigate the response of KNDy neurons to varied glutamate receptor activation. We used calcium imaging to monitor the activity of KNDy neurons in brain slices. We crossed Kiss1-Cre mice—expressing Cre recombinase (Cre) in kisspeptin neurons—with Cre-dependent GCaMP6f mice to generate Kiss1-Cre x GCaMP6f mice that express GCaMP6f in kisspeptin neurons. GCaMP6f fluorescence increases when binding to intracellular calcium and can, thus, be used as an inferential marker of electrical activity. Coronal brain slices (200 µm thickness) obtained from male Kiss1-cre x GCaMP6f mice and containing the arcuate nucleus were placed in a recording chamber under an epifluorescence microscope. KNDy neurons were exposed for 2 minutes to a bath application of either the ionotropic glutamate receptor agonist α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 10µM), the ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA, 50µM), or the group 1 metabotropic glutamate receptor (mGluR) agonist (S)-3,5-dihydroxyphenylglycine (DHPG, 50µM). AMPA, NMDA, and DHPG increased KNDy neuron fluorescence by 7.8±0.5% (n=113 in 7 slices from 6 mice), 7.5±0.5% (n=154 in 6 slices from 5 mice), and 6.1±0.7% (n=159 in 7 slices from 5 mice) respectively. All cells that were excited by NMDA or DHPG were also excited by AMPA. These experiments provide evidence that activation of ionotropic AMPA and NMDA receptors as well as group 1 mGluRs stimulate KNDy neuron activity. Further investigation into the precise role of individual glutamate receptor subtypes on KNDy neuron coordinated activity is needed. Presentation: Friday, June 16, 2023

Bulk RNA-seq and scRNA-seq reveal SLC7A11, a key regulatory molecule of ferroptosis, is a prognostic-related biomarker and highly related to the immune system in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common pathological subtype of lung cancer. Ferroptosis is an iron-dependent, non-apoptotic cell death mode, highly correlated with the tumorigenesis and progression of multiple cancers. Solute carrier family 7 member 11 (SLC7A11) maintains the anti-porter activity of cysteine and glutamate to regulate ferroptosis. We collected bulk RNA-seq and scRNA-seq from The Cancer Genome Altas and Gene Expression Omnibus databases. Then, we extracted the expression level of SLC7A11 to perform the differential expression analysis between normal tissues and LUAD tissues. Then, we applied survival, univariate, and multivariate Cox regression analyses to investigate the predictive value of SLC7A11 in LUAD. Gene set enrichment analysis was used to explore the underlying molecular mechanisms of SLC7A11 in LUAD. Finally, we analyzed the relationship of SLC7A11 to the immune status and the curative effect of immunotherapy. The expression level of SLC7A11 in LUAD tissues was markedly increased. The survival analysis, univariate and multivariate Cox regression analysis showed that SLC7A11 was a negative factor for the prognosis of LUAD patients. Gene set enrichment analysis revealed that several immune-related pathways were enriched in the low-level group. The lower SLC7A11 level has a better therapeutic effect of immunotherapy and less probability of immune escape and dysfunction. SLC7A11 was a prognostic-related biomarker and closely correlated with the immune status and therapeutic effect of immunotherapy in LUAD, which could be an effective biomarker for evaluating the prognosis and the therapeutic efficacy of immunotherapy.