Glutamate-glutamine Cycle Research Articles

Regulatory role of microcystin in the response of microcystin-producing cyanobacteria to elevated CO2: Insights from metabolic profiling

The regulatory role of microcystin in the response of microcystin-producing cyanobacteria to elevated CO2 remains poorly understood. To address this gap, this study compared the responses of wild-type toxic Microcystis PCC 7806 and its mcyB-knockout mutant to elevated CO2 using metabolomic profiling under nitrogen (N)-rich and N-poor conditions. Under N-poor conditions, elevated CO2 promoted carbohydrate synthesis and tricarboxylic acid cycle in both strains, without affecting their growth. Under N-rich conditions, both strains exhibited increased biomass with rising CO2 levels, attributed to enhanced carbohydrate synthesis, tricarboxylic acid cycle, glutamate-glutamine cycle, purine synthesis, and arginine synthesis. However, compared to the mutant, the proliferation of wild-type toxic Microcystis was less stimulated by elevated CO2. The difference was associated with its reduced activity in the pentose phosphate pathway, likely linked to microcystin synthesis. Besides, the difference was related to higher utilization of glutamate, arginine, and aspartate due to increased microcystin production, indicating the regulatory role of microcystin in the response of microcystin-producing cyanobacteria to elevated CO2. Importantly, elevated CO2 could enhance microcystin synthesis by promoting the production of carbon backbones (malonyl CoA), amino acids (including arginine, glutamate and aspartate) and methyl donors (S-adenosylmethionine) of the wild-type toxic Microcystis PCC 7806. Notably, sufficient nitrogen sources were required for increased amino acid and methyl donors synthesis at high CO2 concentration. The discovery revealed underlying mechanisms behind the potential for elevated CO2 levels to increase toxicity risk associated with Microcystis blooms.

Unravelling Neuroinflammation-Mediated Mitochondrial Dysfunction in Mild Cognitive Impairment: Insights from Targeted Metabolomics

BackgroundThe prevalence of Type 2 Diabetes Mellitus (T2DM) is rising rapidly among the elderly due to age-related metabolic changes. Older adults with T2DM have a 50-65% increased risk of developing cognitive impairment, particularly mild cognitive impairment (MCI), which may progress to neurodegenerative conditions like Alzheimer's disease (AD). Recent studies underscore the significant roles of mitochondrial dysfunction, disrupted glutamate-glutamine cycling, hyperglycemia, and hyperprolinemia in cognitive decline. These interconnected metabolites—glucose, glutamine, glutamate, and proline—are potential targets for understanding the relationship between T2DM and cognitive impairment. Material and MethodThe present targeted NMR based metabolomics study aims to compare the blood plasma/serum metabolic profiles of these four metabolites in age and sex matched MCI (N=27) and T2DM patients (N=38) with respect to normal control (NC, N=23) subjects. The metabolic profiling was performed using 1H NMR spectroscopy. ResultsCompared to NC group, both T2DM and MCI groups exhibited elevated glucose levels. Circulatory glucose and glutamine levels were significantly higher in T2DM subjects than in MCI and NC subjects, while glutamate levels followed a similar trend in both T2DM and MCI groups. However, in MCI patients, circulatory proline and proline-to-glutamine (PQR) and glutamate-to-glutamine was significantly elevated compared to T2DM, while glutamine was significantly reduced. ConclusionThe decreased circulatory levels of glutamine and PQR demonstrated statistically significant correlation with the severity of the cognitive impairment as assessed based on Mini Mental State Examination (MMSE) score suggested augmented utilization of glutamine in MCI patients and accumulation to proline due to active neuro-inflammatory processes and impaired mitochondrial functioning in MCI brain.

The Glutamine-Glutamate Cycle Contributes to Behavioral Feminization in Female Rats

Plain Language SummaryThe expression of female sexual behaviors in rodents relies on neuronal signaling within the ventromedial nucleus of the hypothalamus (VMH). Neurons located in the ventral lateral part of the VMH (vlVMH) release glutamate and use it as a mediator to transmit neuronal signals. These neurons are surrounded by astrocytes and may engage in metabolic interactions with them during the perinatal period. Astrocytes produce glutamine (Gln), which are transported into neurons as a precursor for producing glutamate. The vlVMH neurons that release glutamate depend on astrocytic Gln more heavily in female than in male pups. Perinatal disruption of Gln supply to neurons sex-differentially alters glutamate-mediated neuronal signaling and results in morphological changes in vlVMH neurons that resemble those of the opposite sex in adult animals. The present study reveals that perinatal blockade at various points of this metabolic pathway consistently decreased the expression of sex behavior of female rats, while it may only moderately reduce or left unaffected the sex behavior of male rats. Additionally, perinatal inhibition of Gln supply to neurons led to compensatory increases in a neuronal enzyme responsible for glutamate production in the hypothalamus of adult female rats. The results of the study demonstrate that an intact Gln-glutamate metabolic cycle between astrocytes and neurons during the perinatal period is necessary for the development of neuronal networks for proper sex behavior expression in female rats. The findings also suggest that behavioral defeminization could occur in the absence of high levels of E2 exposure in the brain of perinatal female rats.

MTOR inhibition enhances synaptic and mitochondrial function in Alzheimer’s disease in an APOE genotype-dependent manner

Apolipoprotein ε4 (APOE4) carriers develop brain metabolic dysfunctions decades before the onset of Alzheimer’s disease (AD). A goal of the study is to identify if rapamycin, an inhibitor for the mammalian target of rapamycin (mTOR) inhibitor, would enhance synaptic and mitochondrial function in asymptomatic mice with human APOE4 gene (E4FAD) before they showed metabolic deficits. A second goal is to determine whether there may be genetic-dependent responses to rapamycin when compared to mice with human APOE3 alleles (E3FAD), a neutral AD genetic risk factor. We fed asymptomatic E4FAD and E3FAD mice with control or rapamycin diets for 16 weeks from starting from 3 months of age. Neuronal mitochondrial oxidative metabolism and excitatory neurotransmission rates were measured using in vivo 1H-[13C] proton-observed carbon-edited magnetic resonance spectroscopy, and isolated mitochondrial bioenergetic measurements using Seahorse. We found that rapamycin enhanced neuronal mitochondrial function, glutamate-glutamine cycling, and TCA cycle rates in the asymptomatic E4FAD mice. In contrast, rapamycin enhances glycolysis, non-neuronal activities, and inhibitory neurotransmission of the E3FAD mice. These findings indicate that rapamycin might be able to mitigate the risk for AD by enhancing brain metabolic functions for cognitively intact APOE4 carriers, and the responses to rapamycin are varied by APOE genotypes. Consideration of precision medicine may be needed for future rapamycin therapeutics.

Characterization of reduced astrocyte creatine kinase levels in Alzheimer's disease.

The creatine-phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB), in maintaining Adenosine triphosphate (ATP)levels. Alzheimer's disease (AD) has been linked to increased CKB oxidation and loss of its regulatory function, although specific pathological processes and affected cell types remain unclear. In our study, cerebral cortex samples from individuals with AD, dementia with Lewy bodies (DLB), and age-matched controls were analyzed using antibody-based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Combining immunofluorescence (IF) and mass spectrometry (MS), we explored CKB availability in AD and DLB cases. IF and Western blot analysis demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology. However, transcriptomics data and targeted MS demonstrated unaltered total CKB levels, suggesting posttranslational modifications (PTMs) affecting antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment. These findings highlight that the proper function of astrocytes, understudied in the brain compared with neurons, is highly affected by PTMs. Reduction in ATP levels within astrocytes can disrupt ATP-dependent processes, such as the glutamate-glutamine cycle. As CKB and the creatine-phosphocreatine cycle are important in securing constant ATP availability, PTMs in CKB, and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity could be promising biomarkers for monitoring early-stage energy deficits in AD.

Influence of the glutamate-glutamine cycle on valproic acid-associated hepatotoxicity in pediatric patients with epilepsy

Introduction Although valproic acid is generally well tolerated, hepatotoxicity is a common side effect in patients receiving long-term treatment. However, the mechanisms underlying valproic acid-associated hepatotoxicity remain elusive. Methods To investigate the mechanisms and explore the potential risk factors for valproic acid-associated hepatotoxicity, 165 age-matched pediatric patients were recruited for laboratory tests and glutamate-glutamine cycle analysis. Results The concentration of glutamate in patients with hepatotoxicity was significantly greater than that in control patients, while the concentration of glutamine in patients with hepatotoxicity was significantly lower than that in control patients (P <0.05). In addition, the frequencies of the heterozygous with one mutant allele and homozygous with two mutant alleles genotypes in glutamate-ammonia ligase rs10911021 were significantly higher in the hepatotoxicity group than those in the control group (47.1 percent versus 32.5 percent, P = 0.010; 17.6 percent versus 5.2 percent, P = 0.001, respectively). Moreover, heterozygous carriers with one mutant allele and homozygous carriers with two mutant alleles genotypes of glutamate-ammonia ligase rs10911021 exhibited significant differences in the concentrations of glutamine and glutamate concentrations (P ˂ 0.001 and P = 0.001, respectively) and liver function indicators (activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase, P <0.001, respectively). Furthermore, logistic regression analysis indicated that glutamate-ammonia ligase rs10911021 (P = 0.002, odds ratio: 3.027, 95 percent confidence interval, 1.521 − 6.023) and glutamate (P = 0.001, odds ratio: 2.235, 95 percent confidence interval, 1.369 − 3.146) were associated with a greater risk for hepatotoxicity, while glutamine concentrations were negatively associated with hepatotoxicity (P = 0.001, odds ratio: 0.711, 95 percent confidence interval, 0.629 − 0.804). Discussion Understanding pharmacogenomic risks for valproic acid induced hepatotoxicity might help direct patient specific care. Limitations of our study include the exclusive use of children from one location and concomitant medication use in many patients. Conclusion Perturbation of the glutamate-glutamine cycle is associated with valproic acid-associated hepatotoxicity. Moreover, glutamate-ammonia ligase rs10911021, glutamate and glutamine concentrations are potential risk factors for valproic acid-associated hepatotoxicity.

Kallistatin leads to cognition impairment via downregulating glutamine synthetase

In many neurodegenerative disorders, such as Alzheimer's disease (AD), glutamate-mediated neuronal excitotoxicity is considered the basis for cognitive impairment. The mRNA and protein expression of SERPINA4(Kallistatin) are higher in patients with AD. However, whether Kallistatin plays a regulatory role in glutamate-glutamine cycle homeostasis remains unclear. In this study, we identified impaired cognitive function in Kallistatin transgenic (KAL-TG) mice. Baseline glutamate levels were elevated and miniature excitatory postsynaptic current (mEPSC) frequency was increased in the hippocampus, suggesting the impairment of glutamate homeostasis in KAL-TG mice. Mechanistically, we demonstrated that Kallistatin promoted lysine acetylation and ubiquitination of glutamine synthetase (GS) and facilitated its degradation via the proteasome pathway, thereby downregulating GS. Fenofibrate improved cognitive memory in KAL-TG mice by downregulating serum Kallistatin. Collectively, our study findings provide insights the mechanism by which Kallistatin regulates cognitive impairment, and suggest the potential of fenofibrate to prevente and treat of AD patients with high levels of Kallistatin.

Astrocyte-Neuron Interaction via the Glutamate-Glutamine Cycle and Its Dysfunction in Tau-Dependent Neurodegeneration.

Astroglia constitute the largest group of glial cells and are involved in numerous actions that are critical to neuronal development and functioning, such as maintaining the blood-brain barrier, forming synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These properties are deeply affected in the course of many neurodegenerative diseases, including tauopathies, often before the onset of the disease. In this respect, the transfer of essential amino acids such as glutamate and glutamine between neurons and astrocytes in the glutamate-glutamine cycle (GGC) is one example. In this review, we focus on the GGC and the disruption of this cycle in tau-dependent neurodegeneration. A profound understanding of the complex functions of the GGC and, in the broader context, searching for dysfunctions in communication pathways between astrocytes and neurons via GGC in health and disease, is of critical significance for the development of novel mechanism-based therapies for neurodegenerative disorders.

Morphological changes in perisynaptic astrocytes induced by dopamine neuronal degeneration in the striatum of rats

IntroductionThe typical functionality of astrocytes was previously shown to be disrupted by Parkinson's disease (PD), which actively regulates synaptic neurotransmission. However, the morphological changes in astrocytes wrapping glutamatergic synapses in the striatum after dopamine (DA) neuronal degeneration is unclear. MethodsWe utilized a range of methodologies, encompassing the 6-hydroxydopamine (6OHDA)-induced PD model, as well as techniques such as immunohistochemistry, Western blotting, immunofluorescence and immunoelectron microscopy (IEM) to delve into the consequences of DA neuronal degeneration on the morphological attributes of perisynaptic astrocytes. ResultsOur findings demonstrated a notable rise in glial fibrillary acidic protein (GFAP) + astrocyte density and an upregulation in GFAP protein expression within the striatum due to DA neuronal degeneration, coincided with the enlargement, elongation, and thickening of astrocyte protuberances. However, the expression levels of glutamate transporter 1 (GLT1) and glutamine synthetase (GS), which are related to glutamate–glutamine cycle, were significantly reduced. Double immunofluorescence and IEM results indicated that different proportions of vesicular glutamate transporter 1 (VGlut1)+ and vesicular glutamate transporter 2 (VGlut2) + terminals were wrapped by astrocytes. Additionally, DA neuronal degeneration increased the percentage and area of VGlut1+ and VGlut2+ terminals wrapped by GFAP + astrocytes in the striatum. Furthermore, we noted that DA neuronal degeneration increased the percentage of VGlut1+ and VGlut2+ axo-spinous synapses wrapped by astrocytes but had no effect on axo-dendritic synapses. ConclusionHence, perisynaptic astrocytes wrapping striatal glutamatergic synapses exhibit substantial morphological and functional alterations following DA neuronal degeneration making them a potential target for therapeutic interventions in PD.

The role of glutamate and glutamine metabolism and related transporters in nerve cells.

Glutamate and glutamine are the most abundant amino acids in the blood and play a crucial role in cell survival in the nervous system. Various transporters found in cell and mitochondrial membranes, such as the solute carriers (SLCs) superfamily, are responsible for maintaining the balance of glutamate and glutamine in the synaptic cleft and within cells. This balance affects the metabolism of glutamate and glutamine as non-essential amino acids. This review aims to provide an overview of the transporters and enzymes associated with glutamate and glutamine in neuronal cells. We delve into the function of glutamate and glutamine in the nervous system by discussing the transporters involved in the glutamate-glutamine cycle and the key enzymes responsible for their mutual conversion. Additionally, we highlight the role of glutamate and glutamine as carbon and nitrogen donors, as well as their significance as precursors for the synthesis of reduced glutathione (GSH). Glutamate and glutamine play a crucial role in the brain due to their special effects. It is essential to focus on understanding glutamate and glutamine metabolism to comprehend the physiological behavior of nerve cells and to treat nervous system disorders and cancer.

Amino Acid Transporters Proteins Involved in the Glutamate-Glutamine Cycle and Their Alterations in Murine Models of Alzheimer's Disease.

The brain's ability to integrate external stimuli and generate responses is highly complex. While these mechanisms are not completely understood, current evidence suggests that alterations in cellular metabolism and microenvironment are involved in some dysfunctions as complex as Alzheimer's disease. This pathology courses with defects in the establishment of chemical synapses, which is dependent on the production and supply of neurotransmitters like glutamate and its recycling through the glutamate-glutamine cycle. Alterations in the expression and function of the amino acid transporters proteins involved in this cycle have recently been reported in different stages of Alzheimer's disease. Most of these data come from patients in advanced stages of the disease or post-mortem, due to the ethical and technical limitations of human studies. Therefore, genetically modified mouse models have been an excellent tool to analyze metabolic and even behavioral parameters that are very similar to those that develop in Alzheimer's disease, even at presymptomatic stages. Hence, this paper analyzes the role of glutamate metabolism and its intercellular trafficking in excitatory synapses from different approaches using transgenic mouse models; such an analysis will contribute to our present understanding of AD.

Long-term intake of thermo-induced oxidized oil results in anxiety-like and depression-like behaviors: involvement of microglia and astrocytes.

Frequent consumption of fried foods has been strongly associated with a higher risk of anxiety and depression, particularly among young individuals. The existing evidence has indicated that acrylamide produced from starchy foods at high temperatures can induce anxious behavior. However, there is limited research on the nerve damage caused by thermo-induced oxidized oil (TIOO). In this study, we conducted behavioral tests on mice and found that prolonged consumption of TIOO led to significant anxiety behavior and a tendency toward depression. TIOO primarily induced these two emotional disorders by affecting the differentiation of microglia, the level of inflammatory factors, the activation of astrocytes, and glutamate circulation in brain tissue. By promoting the over-differentiation of microglia into M1 microglia, TIOO disrupted their differentiation balance, resulting in an up-regulation of inflammatory factors (IL-1β, IL-6, TNF-α, NOS2) in M1 microglia and a down-regulation of neuroprotective factors IL-4/IL-10 in M2 microglia, leading to nerve damage. Moreover, TIOO activated astrocytes, accelerating their proliferation and causing GFAP precipitation, which damaged astrocytes. Meanwhile, TIOO stimulates the secretion of the BDNF and reduces the level of the glutamate receptor GLT-1 in astrocytes, leading to a disorder in the glutamate-glutamine cycle, further exacerbating nerve damage. In conclusion, this study suggests that long-term intake of thermo-induced oxidized oil can trigger symptoms of anxiety and depression.

HIV-1 gp120 Induces Glutamate Excitotoxicity By Diminishing Glutamine Synthetase Expression in Astrocytes

Background： As the most abundant subtype of glial cells, astrocytes have an important role in maintaining homeostasis in the central nervous system(CNS) by regulating neurotransmitters. Glutamate is an excitatory neurotransmitter released from neurons, while astrocytes take up glutamate and mediate the conversion to glutamine, which is known as the glutamate-glutamine cycle between neurons and astrocytes. Glutamine synthetase (GS) is found primarily in astrocytes and is a key player in the glutamate-glutamine cycle. GS synthesizes glutamine using glutamate and contributes to the maintenance of glutamate homeostasis between neurons and astrocytes by facilitating glutamate clearance. In addition, glutamate excitotoxicity is a key pathological factor in neurodegenerative pathologies such as HIV-1-associated neurocognitive disorder (HAND) and Alzheimer's disease. Although the importance of GS in the glutamate-glutamine cycle has been demonstrated, the relationship between gp120 in regulating astrocyte glutamate metabolism and GS activity is unclear. Methods: To evaluate the glutamate clearance capacity, glutamate uptake assay was undertaken by using the glutamate colorimetric assay kit. Astrocytes (u251) were incubated for 24 hours with different concentrations of full-length HIV-1 gp120 and medium in each dish was replaced with serum-free HBSS that containing 2 mM glutamate. After 10, 30, 60, or 120 min in the incubator, 200 μL culture supernatants of the astrocytes were collected and mixed with the corresponding reagents provided in the kit as required by the protocol, then 100 μL of the mixed solution were transferred to each well of the 96-well culture plates. The absorbance of the mixed solution was measured at 340 nm using a microplate reader. The glutamate content of each sample was calculated according to the formula provided in the instruction manual. The expressions of GS in astrocytes which were incubated for 24 hours with different concentrations of full-length HIV-1 gp120 were detected by Western blot. Student's t-tests and ANOVA were applied to determine statistical significance. Results： The glutamate uptake assay reflects whether the glutamate uptake capacity of astrocytes is impaired by assessing the extracellular glutamate content. First, changes in extracellular glutamate content were detected by treating astrocytes with different concentrations of HIV-1 gp120 for 24h. As expected, the extracellular glutamate content increased relative to the blank control, indicating that HIV-1 gp120 impaired the glutamate uptake ability of astrocytes. The optimal experimental point to test the glutamate uptake capacity was 30 min after the addition of serum-free HBSS that containing 2 mM glutamate by time-point experiments. In addition, the results of western blot showed that GS expression in astrocytes was significantly decreased by HIV-1 gp120 treatment. The GS expression levels and glutamate uptake assay results followed the same trend. Conclusion: In conclusion, this study explored the specific mechanisms of glutamatergic excitotoxicity in the brains of HAND patients. HIV-1 gp120 could impair the glutamate uptake capacity of astrocytes by diminishing GS expression. ( Acknowledgements: National Natural Science Foundation of China, No. 82172259 to H.C.; Corresponding author: Hong Cao, gzhcao@smu.edu.cn )

Aspartic Acid in Health and Disease.

Aspartic acid exists in L- and D-isoforms (L-Asp and D-Asp). Most L-Asp is synthesized by mitochondrial aspartate aminotransferase from oxaloacetate and glutamate acquired by glutamine deamidation, particularly in the liver and tumor cells, and transamination of branched-chain amino acids (BCAAs), particularly in muscles. The main source of D-Asp is the racemization of L-Asp. L-Asp transported via aspartate-glutamate carrier to the cytosol is used in protein and nucleotide synthesis, gluconeogenesis, urea, and purine-nucleotide cycles, and neurotransmission and via the malate-aspartate shuttle maintains NADH delivery to mitochondria and redox balance. L-Asp released from neurons connects with the glutamate-glutamine cycle and ensures glycolysis and ammonia detoxification in astrocytes. D-Asp has a role in brain development and hypothalamus regulation. The hereditary disorders in L-Asp metabolism include citrullinemia, asparagine synthetase deficiency, Canavan disease, and dicarboxylic aminoaciduria. L-Asp plays a role in the pathogenesis of psychiatric and neurologic disorders and alterations in BCAA levels in diabetes and hyperammonemia. Further research is needed to examine the targeting of L-Asp metabolism as a strategy to fight cancer, the use of L-Asp as a dietary supplement, and the risks of increased L-Asp consumption. The role of D-Asp in the brain warrants studies on its therapeutic potential in psychiatric and neurologic disorders.

MNSCs overexpressing Rimkla transplantation facilitates cognitive recovery in a mouse model of traumatic brain injury

N-acetyl aspartyl-glutamate (NAAG) is easily inactivated for the hydrolysis of NAAG peptidase on the surface of glial cells, thereby losing its endogenous neuroprotective effect after traumatic brain injury. In this study, lentiviral vectors were used to over express/knock out NAAG synthetase II (Rimkla) in mouse embryonic neural stem cells (mNSCs) invitro and these mNSCs were transplanted at the lesion site in a mouse model of controlled cortical impact (CCI). Invivo experiments showed that transplantation of mNSCs overexpressing Rimkla regulated glutamate-glutamine cycling between adjacent astrocytes and neurons in the subacute phase of CCI, thereby enhancing support for neuronal metabolism and promoting neuronal synaptic repair in the hippocampal CA3 region. Taken together, these findings demonstrate that transplantation of neural stem cells overexpressing Rimkla can effectively increase the NAAG concentration in local brain regions, which opens up new ideas for the maintenance of NAAG neuroprotective effects after TBI.

Memantine Improves the Disturbed Glutamine and γ-Amino Butyric Acid Homeostasis in the Brain of Rats Subjected to Experimental Autoimmune Encephalomyelitis.

Glutamine (Gln), glutamate (Glu), and γ-amino butyric acid (GABA) are essential amino acids for brain metabolism and function. Astrocyte-derived Gln is the precursor for the two most important neurotransmitters in the central nervous system (CNS), which are the excitatory neurotransmitter Glu and the inhibitory neurotransmitter GABA. In addition to their roles in neurotransmission, these amino acids can be used as alternative substrates in brain metabolism that enable metabolic coupling between astrocytes and neurons in the glutamate-glutamine cycle (GGC). The disturbed homeostasis of these amino acids within the tripartite synapse may be involved in the pathogenesis of various neurological diseases. Interactions between astrocytes and neurons in terms of Gln, Glu, and GABA homeostasis were studied in different phases of experimental allergic encephalomyelitis (EAE) in Lewis rats. The results of the study showed a decrease in the transport (uptake and release) of Gln and GABA in both neuronal and astrocyte-derived fractions. These effects were fully or partially reversed when the EAE rats were treated with memantine, a NMDA receptor antagonist. Changes in the expression and activity of selected glutamine/glutamate metabolizing enzymes, such as glutamine synthase (GS) and phosphate-activated glutaminase (PAG), which were affected by memantine, were observed in different phases of EAE. The results suggested perturbed homeostasis of Gln, Glu, and GABA during EAE, which may indicate alterations in neuron-astrocyte coupling and dysfunction of the tripartite synapse. Memantine appears to partially regulate the disturbed relationships between Gln, Glu, and GABA.

Metabolic partitioning in the brain and its hijacking by glioblastoma.

The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.

Mutant Tau protein-induced abnormalities in the Na+-dependent glutamine translocation and recycling and their impact on astrocyte-neuron integrity in vitro

Tau-dependent neurodegeneration is accompanied by astrocytosis in a mouse trans-genic model, which replicates the neuropathological characteristic of tauopathy and other human neurodegenerative disorders where astrocyte activation precedes neuronal loss and is associated with disease progression. This indicates an important role of astrocytes in the development of the disease. Astrocytes derived from a transgenic mouse model expressing human Tau, exhibit changes in cellular markers of astrocyte neuroprotective function related to the glutamate-glutamine cycle (GGC), representing a key part of astrocyte-neuron integrity. Here, we focused on investigating the functional properties of key GGC components involved in the astrocyte-neuron network associated with Tau pathology in vitro. Mutant recombinant Tau (rTau) carrying the P301L mutation was added to the neuronal cultures, with or without control astrocyte-conditioned medium (ACM), to study glutamine translocation through the GGC. We demonstrated that mutant Tau in vitro induces neuronal degeneration, while control astrocytes response in neuroprotective way by preventing neurodegeneration. In parallel with this observation, we noticed the Tau-dependent decline of neuronal microtubule associated protein 2 (MAP2), followed by changes in glutamine (Gln) transport. Exposure to rTau decreases sodium-dependent Gln uptake in neurons and that effect was reversed when cells were co-incubated with control ACM after induction of rTau dependent pathology. Further, we found that neuronal Na+-dependent system A is the most specific system that is affected under rTau exposure. In addition, in rTau-treated astrocytes total Na+-dependent uptake of Gln, which is mediated by the N system, increases. Altogether, our study suggest mechanisms operating in Tau pathology may be related to the alterations in glutamine transport and recycling that affect neuronal-astrocytic integrity.

Ceftriaxone improves impairments in synaptic plasticity and cognitive behavior in APP/PS1 mouse model of Alzheimer's disease by inhibiting extrasynaptic NMDAR-STEP61 signaling.

Abnormal activation of the extrasynaptic N-methyl-d-aspartate receptor (NMDAR) contributes to the pathogenesis of Alzheimer's disease (AD). Ceftriaxone (Cef) can improve cognitive impairment by upregulating glutamate transporter-1 and promoting the glutamate-glutamine cycle in an AD mouse model. This study aimed to investigate the effects of Cef on synaptic plasticity and cognitive-behavioral impairment and to unravel the associated underlying mechanisms. We used an APPswe/PS1dE9 (APP/PS1) mouse model of AD in this study. Extrasynaptic components from hippocampal tissue homogenates were isolated using density gradient centrifugation. Western blot was performed to evaluate the expressions of extrasynaptic NMDAR and its downstream elements. Intracerebroventricular injections of adeno-associated virus (AAV)-striatal enriched tyrosine phosphatase 61 (STEP61 ) and AAV-STEP61 -shRNA were used to modulate the expressions of STEP61 and extrasynaptic NMDAR. Long-term potentiation (LTP) and Morris water maze (MWM) tests were performed to evaluate the synaptic plasticity and cognitive function. The results showed that the expressions of GluN2B and GluN2BTyr1472 in the extrasynaptic fraction were upregulated in AD mice. Cef treatment effectively prevented the upregulation of GluN2B and GluN2BTyr1472 expressions. It also prevented changes in the downstream signals of extrasynaptic NMDAR, including increased expressions of m-calpain and phosphorylated p38 MAPK in AD mice. Furthermore, STEP61 upregulation enhanced, whereas STEP61 downregulation reduced the Cef-induced inhibition of the expressions of GluN2B, GluN2BTyr1472 , and p38 MAPK in the AD mice. Similarly, STEP61 modulation affected Cef-induced improvements in induction of LTP and performance in MWM tests. In conclusion, Cef improved synaptic plasticity and cognitive behavioral impairment in APP/PS1 AD mice by inhibiting the overactivation of extrasynaptic NMDAR and STEP61 cleavage due to extrasynaptic NMDAR activation.

Role of Astrocytes in Epilepsy and Schizophrenia

The dangers of epilepsy and schizophrenia are increasingly being noticed. Its economic burden, social harm and harm to patients cannot be ignored. However, little is known about the pathogenesis of psychiatric disorders. Relevant treatment is limited to symptomatic treatment. Research suggests astrocytes play a role in seizures and schizophrenia. In the occurrence and development of mental diseases such as epilepsy and schizophrenia, astrocytes cannot be ignored. The article introduces the current findings and theories on role and function of astrocytes, and their connection with epilepsy and schizophrenia. It describes the positive effects and negative effects of astrocytes and their basic mechanisms that are now believed. And those mechanisms include glutamate-glutamine cycle which is related to the synthesizing of gama-aminobutyric acid (GABA), blood brain barrier which is controlling the matter exchange between vessels and brain, several molecules and inflammatory factors effect on the channel expressing on the surface of astrocytes and other main paths that could contribute to neuronal disorders. The article also includes several chemicals and their effects on inhibiting astrocytes of isolated sample, from chliroquine, calmodulin-trifluoperazin, gamma globulin and anticardiolipin antibodies. Last, the present study on the relationship between epilepsy and schizophrenia is discussed.