Glutamate Receptors In Brain Research Articles

The glutamatergic system in Alzheimer's disease: a systematic review with meta-analysis.

Glutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer's disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta-analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain. We searched PubMed and Web of Science (database origin-October 2023) reports evaluating glutamate, glutamine, glutaminase, glutamine synthetase, glutamate reuptake, aspartate, excitatory amino acid transporters, vesicular glutamate transporters, glycine, D-serine, metabotropic and ionotropic glutamate receptors in the AD human brain (PROSPERO #CDRD42022299518). The studies were synthesized by outcome and brain region. We included cortical regions, the whole brain (cortical and subcortical regions combined), the entorhinal cortex and the hippocampus. Pooled effect sizes were determined with standardized mean differences (SMD), random effects adjusted by false discovery rate, and heterogeneity was examined by I2 statistics. The search retrieved 6 936 articles, 63 meeting the inclusion criteria (N = 709CN/786AD; mean age 75/79). We showed that the brain of AD individuals presents decreased glutamate (SMD = -0.82; I2 = 74.54%; P < 0.001) and aspartate levels (SMD = -0.64; I2 = 89.71%; P = 0.006), and reuptake (SMD = -0.75; I2 = 83.04%; P < 0.001. We also found reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-GluA2/3 levels (SMD = -0.63; I2 = 95.55%; P = 0.046), hypofunctional N-methyl-D-aspartate receptor (NMDAR) (SMD = -0.60; I2 = 91.47%; P < 0.001) and selective reduction of NMDAR-GluN2B subunit levels (SMD = -1.07; I2 = 41.81%; P < 0.001). Regional differences include lower glutamate levels in cortical areas and aspartate levels in cortical areas and in the hippocampus, reduced glutamate reuptake, reduced AMPAR-GluA2/3 in the entorhinal cortex, hypofunction of NMDAR in cortical areas, and a decrease in NMDAR-GluN2B subunit levels in the entorhinal cortex and hippocampus. Other parameters studied were not altered. Our findings show depletion of the glutamatergic system and emphasize the importance of understanding glutamate-mediated neurotoxicity in AD. This study has implications for the development of therapies and biomarkers in AD.

Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior.

Clinical studies provide evidence that ketamine and psilocybin could be used as fast-acting antidepressants, though their mechanisms and toxicity are still not fully understood. To address this issue, we have examined the effect of a single administration of ketamine and psilocybin on the extracellular levels of neurotransmitters in the rat frontal cortex and reticular nucleus of the thalamus using microdialysis. The genotoxic effect and density of glutamate receptor proteins was measured with comet assay and Western blot, respectively. An open field test, light–dark box test and forced swim test were conducted to examine rat behavior 24 h after drug administration. Ketamine (10 mg/kg) and psilocybin (2 and 10 mg/kg) increased dopamine, serotonin, glutamate and GABA extracellular levels in the frontal cortex, while psilocybin also increased GABA in the reticular nucleus of the thalamus. Oxidative DNA damage due to psilocybin was observed in the frontal cortex and from both drugs in the hippocampus. NR2A subunit levels were increased after psilocybin (10 mg/kg). Behavioral tests showed no antidepressant or anxiolytic effects, and only ketamine suppressed rat locomotor activity. The observed changes in neurotransmission might lead to genotoxicity and increased NR2A levels, while not markedly affecting animal behavior.

Glutamatergic receptor expression changes in the Alzheimer's disease hippocampus and entorhinal cortex.

Alzheimer's Disease (AD) is the leading form of dementia worldwide. Currently, the pathological mechanisms underlying AD are not well understood. Although the glutamatergic system is extensively implicated in its pathophysiology, there is a gap in knowledge regarding the expression of glutamate receptors in the AD brain. This study aimed to characterize the expression of specific glutamate receptor subunits in post‐mortem human brain tissue using immunohistochemistry and confocal microscopy. Free‐floating immunohistochemistry and confocal laser scanning microscopy were used to quantify the density of glutamate receptor subunits GluA2, GluN1, and GluN2A in specific cell layers of the hippocampal sub‐regions, subiculum, entorhinal cortex, and superior temporal gyrus. Quantification of GluA2 expression in human post‐mortem hippocampus revealed a significant increase in the stratum (str.) moleculare of the dentate gyrus (DG) in AD compared with control. Increased GluN1 receptor expression was found in the str. moleculare and hilus of the DG, str. oriens of the CA2 and CA3, str. pyramidale of the CA2, and str. radiatum of the CA1, CA2, and CA3 subregions and the entorhinal cortex. GluN2A expression was significantly increased in AD compared with control in the str. oriens, str. pyramidale, and str. radiatum of the CA1 subregion. These findings indicate that the expression of glutamatergic receptor subunits shows brain region‐specific changes in AD, suggesting possible pathological receptor functioning. These results provide evidence of specific glutamatergic receptor subunit changes in the AD hippocampus and entorhinal cortex, indicating the requirement for further research to elucidate the pathophysiological mechanisms it entails, and further highlight the potential of glutamatergic receptor subunits as therapeutic targets.

Activation and deactivation steps in the tryptophan breakdown pathway in major depressive disorder: A link to the monocyte inflammatory state of patients

It is unclear how the tryptophan (TRP) breakdown pathway relates to the activated inflammatory state of patients with major depressive disorder (MDD).We determined in two different cohorts of patients with MDD (n = 281) and healthy controls (HCs) (n = 206) collected for the EU-MOODINFLAME project:a.)the monocyte expression levels of 5 key pro-inflammatory cytokine/chemokine genes (ICCGs), 5 type I interferon stimulated genes (ISGs), and 4 kynurenine pathway (KP) enzyme genes (i.e. IDO-1, KMO, CCBL1/KAT II and CCBL2/KAT III) by standard q-PCR,b.)serum levels of TRP, 5-HTrp, 5-HIAA, KYN, KYNA, 3-HK, XA, PIC, and QUIN by LC-MS/MS and/or HPLC, and calculated various TRP/KP metabolism ratios.We then correlated outcomes to each other, and to the clinical characteristics of patients.Both cohorts of patients differed clinically; patients of the Munich cohort (n = 50) were less overweight, less medicated, were less in the current episode and showed a higher HAM-D 17 score as compared with patients of the Muenster cohort (n = 231).An increased expression of ICCGs was found in the circulating monocytes of patients of both cohorts; this was in particular evident in the Munich cohort. In contrast, ISGs monocyte expression levels tended to be reduced (both cohorts).TRP serum levels were linked to the pro-inflammatory (ICCGs) monocyte state of patients; a decrease in TRP serum levels was found in the Munich cohort; TRP levels correlated negatively to patient's HAM-D 17 score. Contrary to what expected, KYN serum levels were not increased in patients (both cohorts); and an increased KYN/TRP ratio was only found in the Munich patients (who showed the lowest TRP serum levels). IDO-1 monocyte expression levels were decreased in patients (both cohorts) and negatively associated to their pro-inflammatory (ICCGs) monocyte state. Thus, a depletion of TRP via an ICCGs-inflammatory IDO activation is not likely in MDD.Downstream from KYN, and regarding compounds influencing glutamate receptors (GR), reduced serum levels of KYNA (NMDA-R antagonist), 3-HK (NMDA-R agonist), and XA (mGlu2/3 agonist) were found in patients of both cohorts; PIC serum levels (NMDA-R antagonist) were increased in patients of both cohorts. Reduced QUIN serum levels (NMDA-R agonist) were found in patients of the Muenster cohort,only. 3-HK levels correlated to the monocyte inflammatory ICCG state of patients. The ultimate effect on brain glutamate receptor triggering of this altered equilibrium between peripheral agonists and antagonists remains to be elucidated.

Associations among peripheral and central kynurenine pathway metabolites and inflammation in depression.

Kynurenine pathway (KP) metabolites are believed to be a link between inflammation and depression through effects on brain glutamate receptors. However, neither the relationship between plasma and cerebrospinal fluid (CSF) KP metabolites nor their association with inflammatory mediators is well-established in depression. Moreover, the clinical profile associated with combined activation of plasma inflammatory and kynurenine pathways is unknown. Accordingly, plasma and CSF-KP metabolites and inflammatory markers along with depressive symptoms and antidepressant treatment response were measured in 72 unmedicated depressed patients. Following bivariate analyses, component factors representing immune and kynurenine variables in the plasma and CSF were extracted and were used to examine directionality of associations in a path model. In addition, patients were clustered using individual markers that most accounted for the association between plasma immune and KP systems. Path analysis revealed a directional association extending from plasma inflammatory markers to plasma kynurenines, to CSF kynurenines. Among immune markers, plasma tumor necrosis factor (TNF) was robustly associated with plasma kynurenine (KYN) and KYN/tryptophan (TRP), which was in turn significantly associated with CSF KYN, kynurenic acid, and quinolinic acid. Clustering of patients based on plasma TNF and KYN/TRP yielded subgroups of high (N = 17) and low (N = 55) TNF-KYN/TRP groups. High TNF-KYN/TRP subjects exhibited greater depression severity, anhedonia, and treatment nonresponse. In conclusion, plasma-KP metabolites may mediate an inflammation-associated depressive symptom profile via CNS KP metabolites that can serve as a target for intervention at the level of inflammation, peripheral KYN metabolism, KYN transport to the brain, or effects of KP metabolites on glutamate receptors.

Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain.

In the cerebellum, GluD2 is exclusively expressed in Purkinje cells, where it regulates synapse formation and regeneration, synaptic plasticity, and motor learning. Delayed cognitive development in humans with GluD2 gene mutations suggests extracerebellar functions of GluD2. However, extracerebellar expression of GluD2 and its relationship with that of GluD1 are poorly understood. GluD2 mRNA and protein were widely detected, with relatively high levels observed in the olfactory glomerular layer, medial prefrontal cortex, cingulate cortex, retrosplenial granular cortex, olfactory tubercle, subiculum, striatum, lateral septum, anterodorsal thalamic nucleus, and arcuate hypothalamic nucleus. These regions were also enriched for GluD1, and many individual neurons coexpressed the two GluDs. In the retrosplenial granular cortex, GluD1 and GluD2 were selectively expressed at PSD-95-expressing glutamatergic synapses, and their coexpression on the same synapses was shown by SDS-digested freeze-fracture replica labeling. Biochemically, GluD1 and GluD2 formed coimmunoprecipitable complex formation in HEK293T cells and in the cerebral cortex and hippocampus. We further estimated the relative protein amount by quantitative immunoblotting using GluA2/GluD2 and GluA2/GluD1 chimeric proteins as standards for titration of GluD1 and GluD2 antibodies. Intriguingly, the relative amount of GluD2 was almost comparable to that of GluD1 in the postsynaptic density fraction prepared from the cerebral cortex and hippocampus. In contrast, GluD2 was overwhelmingly predominant in the cerebellum. Thus, we have determined the relative extracerebellar expression of GluD1 and GluD2 at regional, neuronal, and synaptic levels. These data provide a molecular-anatomical basis for possible competitive and cooperative interactions of GluD family members at synapses in various brain regions.

Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain

Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain

Sequential Changes in Brain Glutamate and Adenosine A1 Receptors May Explain Severity of Adolescent Alcohol Withdrawal after Consumption of High Levels of Alcohol.

There is an excellent correlation between the age when alcohol consumption begins and the likelihood of lifelong problems with alcohol abuse. Alcohol use often begins in adolescence, a time marked by brain development and maturation of numerous brain systems. Rats are an important model, wherein the emergence of alcohol withdrawal symptoms serves as a gauge of dependency following chronic alcohol consumption. Previous work has shown that adolescent Long-Evans rats consume high levels of alcohol and develop a severe alcohol withdrawal syndrome when fed alcohol as part of a liquid diet. Acutely, alcohol inhibits two important excitatory receptors for glutamate (NMDA and AMPA) and may further decrease glutamate activity through modulatory adenosine receptors. The present study focuses on potential adaptive changes in expression of these receptors that may create a receptor imbalance during chronic alcohol consumption and lead to severe overexcitation of the adolescent brain during alcohol withdrawal. Levels of brain expression of NMDA, AMPA, and adenosine A1 and A2a receptors were determined by Western blotting after adolescent rats consumed an alcohol-containing liquid diet for 4, 11, or 18 days. Severity of alcohol withdrawal was also assessed at these time points. Levels increased for both AMPA and NMDA receptors, significant and approaching maximal by day 11. In contrast, A1 receptor density showed a slow decline reaching significance at 18 days. There were no changes in expression of adenosine A2a receptor. The most severe withdrawal symptoms appear to coincide with the later downregulation of adenosine A1 receptors coming on top of maximal upregulation of excitatory AMPA and NMDA glutamate receptors. Thus, loss of adenosine “brakes” on glutamate excitation may punctuate receptor imbalance in alcohol-consuming adolescents by allowing the upregulation of the excitatory receptors to have full impact during early alcohol withdrawal.

Electron Acceptive Mass Tag for Mass Spectrometric Imaging-Guided Synergistic Targeting to Mice Brain Glutamate Receptors.

Dysfunctional glutamate receptors (GluRs) have been implicated in neurological disorders and injuries. Hetero-tetrameric assemblies of different GluR subunits or splicing variants have distinct spatiotemporal expression patterns and pharmacological properties. Mass spectrometric imaging of GluRs-targeted small molecules is important for determining the regional preferences of these compounds. We report herein the development of a mass tag covalently bonded with glutamate or N-methyl-d-aspartate that functions as both an electron acceptor to generate mass spectrometric signals on irradiated (Bi2O3)0.07(CoO)0.03(ZnO)0.9 nanoparticles with the third harmonic (355 nm) of Nd3+:YAG laser and as the core component to target bilobed clamshell-like structures of GluRs. In this approach, different molecules produce the same tag ion. It provides a new avenue for quantitative assessment of spatial densities of different compounds, which cannot be achieved with well-established stable isotope labeling technique due to different ionization efficiency of different compounds. Various coexisting endogenous molecules are also simultaneously detected for investigation of overall physiological changes induced by these compounds. Because semiconductors do not generate background peaks, this method eliminates interferences from organic matrix materials that are used in regular MALDI (matrix assisted laser desorption ionization). The localized ionization provides high spatial resolution that can be down to sub-micrometers.

Anatomy and Physiology of Metabotropic Glutamate Receptors in Mammalian and Avian Auditory System.

Glutamate, as the major excitatory neurotransmitter used in the vertebrate brain, activates ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs), which mediate fast and slow neuronal actions, respectively. mGluRs play important modulatory roles in many brain areas, forming potential targets for drugs developed to treat brain disorders. Here, we review studies on mGluRs in the mammalian and avian auditory system. Although anatomical expression of mGluRs in the cochlear nucleus has been well characterized, data for other auditory nuclei await more systematic investigations especially at the electron microscopy level. The physiology of mGluRs has been extensively studied using in vitro brain slice preparations, with a focus on the auditory circuitry in the brainstem. These in vitro physiological studies have demonstrated that mGluRs participate in synaptic transmission, regulate ionic homeostasis, induce synaptic plasticity, and maintain the balance between Excitation and Inhibition (E/I) in a variety of auditory structures. However, the modulatory roles of mGluRs in auditory processing remain largely unclear at the system and behavioral levels, and the functions of mGluRs in auditory disorders remain entirely unknown.

Phaseic Acid, an Endogenous and Reversible Inhibitor of Glutamate Receptors in Mouse Brain

Phaseic acid (PA) is a phytohormone regulating important physiological functions in higher plants. Here, we show the presence of naturally occurring (-)-PA in mouse and rat brains. (-)-PA is exclusively present in the choroid plexus and the cerebral vascular endothelial cells. Purified (-)-PA has no toxicity and protects cultured cortical neurons against glutamate toxicity through reversible inhibition of glutamate receptors. Focal occlusion of the middle cerebral artery elicited a significant induction in (-)-PA expression in the cerebrospinal fluid but not in the peripheral blood. Importantly, (-)-PA induction only occurred in the penumbra area, indicting a protective role of PA in the brain. Indeed, elevating the (-)-PA level in the brain reduced ischemic brain injury, whereas reducing the (-)-PA level using a monoclonal antibody against (-)-PA increased ischemic injury. Collectively, these studies showed for the first time that (-)-PA is an endogenous neuroprotective molecule capable of reversibly inhibiting glutamate receptors during ischemic brain injury.

Lysine mediation of neuroendocrine food regulation in guinea fowl

In poultry, obesity is partly influenced by food intake, and is increasingly becoming a nationwide problem. Hypothalamic food intake mechanisms are involved metabolically and neurologically via two peptide hormones, leptin and ghrelin, and the amino acid glutamate, which is enzymatically derived from lysine metabolism. We hypothesize that lysine homeostasis mediates regulation of feed intake and performance characteristics via the brain-liver axis through glutamate sensing. The objective was to examine the effects of lysine homeostasis in avian food regulation and performance through neuroendocrine signaling. One-day-old male French Guinea fowl (GF) keets (n = 270) were weighed and randomly assigned to 5 dietary treatments (0.80%, 0.86%, 0.92%, 1.10% control, and 1.22% lysine) in 3 replicates. At 4 and 8 wk of age 20% of experimental birds were randomly selected, weighed and euthanatized. The liver, pancreas, and hypothalamus were excised, snap frozen in liquid nitrogen and stored at -80°C until use. Tissue mRNA was extracted and cDNA synthesized for qPCR assays. Lysine at 0.80 and 0.86% hindered growth, development of digestive organs, expression of brain and liver glutamate and leptin receptors, and caused high mortality in GF. The fold change for metabotropic glutamate receptor I was lower (P < 0.05) in liver and higher in brain at 0.86 and 0.92% than the control (1.10%) and 1.22% lysine. The 1.22% lysine exhibited highest expression of ionotropic glutamate receptor, while brain ghrelin receptor expression was highest at 0.86 and 0.92% lysine. Therefore, dietary lysine concentration may influence signaling pathways regulating food intake in brain-liver axis via glutamate synthesis.

Costimulation of AMPA and metabotropic glutamate receptors underlies phospholipase C activation by glutamate in hippocampus.

Glutamate, a major neurotransmitter in the brain, activates ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs, respectively). The two types of glutamate receptors interact with each other, as exemplified by the modulation of iGluRs by mGluRs. However, the other way of interaction (i.e., modulation of mGluRs by iGluRs) has not received much attention. In this study, we found that group I mGluR-specific agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) alone is not sufficient to activate phospholipase C (PLC) in rat hippocampus, while glutamate robustly activates PLC. These results suggested that additional mechanisms provided by iGluRs are involved in group I mGluR-mediated PLC activation. A series of experiments demonstrated that glutamate-induced PLC activation is mediated by mGluR5 and is facilitated by local Ca(2+) signals that are induced by AMPA-mediated depolarization and L-type Ca(2+) channel activation. Finally, we found that PLC and L-type Ca(2+) channels are involved in hippocampal mGluR-dependent long-term depression (mGluR-LTD) induced by paired-pulse low-frequency stimulation, but not in DHPG-induced chemical LTD. Together, we propose that AMPA receptors initiate Ca(2+) influx via the L-type Ca(2+) channels that facilitate mGluR5-PLC signaling cascades, which underlie mGluR-LTD in rat hippocampus.

Retraction: Radenovic L, Selakovic V. Mitochondrial superoxide production and MnSOD activity following exposure to an agonist and antagonists of ionotropic receptors in rat brain, Arch Biol Sci. 2005; 57(1):1-10, DOI:10.2298/ABS0501001R

This is a notice of retraction of the article: Mitochondrial superoxide production and MnSOD activity following exposure to an agonist and antagonists of ionotropic glutamate receptors in rat brain, published in the Archives of Biological Sciences in 2005, Vol. 57, Issue 1. The Editor-in-Chief has been informed that this paper plagiarizes an earlier paper: Radenovic L, Selakovic V, Kartelija G, Todorovic N, Nedeljkovic M. Differential effects of NMDA and AMPA/kainate receptor antagonists on superoxide production and MnSOD activity in rat brain following intrahippocampal injection. Brain Res Bull, 2004, 64(1):85-93. This claim is correct and almost the entire paper is a verbatim copy of the earlier one. After confirmation of this fact, the Editor-in-Chief of the Archives of Biological Sciences has decided to retract the paper immediately. We apologize to the readers of the journal that it took so many years to notice this error and to retract the paper. We request readers of the journal to directly get in touch with the editorial office and the editors of the journal for similar cases in the future, so that they can be handled promptly. &lt;br&gt;&lt;br&gt;&lt;font color="red"&gt;&lt;b&gt; Link to the retracted article &lt;u&gt;&lt;a href="http://dx.doi.org/10.2298/ABS0501001R"&gt;10.2298/ABS0501001R&lt;/a&gt;&lt;/b&gt;&lt;/u&gt;

Making excitatory synapses slow (or fast)

Neuroscience![Figure][1] Glutamate release in a neuronal synapse. ILLUSTRATION; V. ALTOUNIAN/ SCIENCE Glutamate is the most widely used neurotransmitter in the brain. Glutamate receptors in the mammalian brain are macromolecular complexes assembled from a pool of different proteins. Several proteins in these complexes, including cornichon homolog 2 (CNIH2), are known to influence the workings of certain glutamate receptors of the AMPA type, but their precise roles are unknown. Boudkkazi et al. recorded synaptic transmission between hippocampal neurons and inhibited CNIH2 expression with small interfering RNAs to investigate the role CNIH2 plays at different synapses. They found that CNIH2 profoundly affected the timing of synaptic transmission—CNIH2 slowed things down, whereas its absence sped things up. Such careful kinetic regulation is necessary because speed is more important for some tasks, whereas reliability, the successful transmission of a signal across the synapse, is more important for others. Neuron 82 , 848 (2014). [1]: pending:yes

The function of spermine

Polyamines play important roles in cell physiology including effects on the structure of cellular macromolecules, gene expression, protein function, nucleic acid and protein synthesis, regulation of ion channels, and providing protection from oxidative damage. Vertebrates contain two polyamines, spermidine and spermine, as well as their precursor, the diamine putrescine. Although spermidine has an essential and unique role as the precursor of hypusine a post-translational modification of the elongation factor eIF5A, which is necessary for this protein to function in protein synthesis, no unique role for spermine has been identified unequivocally. The existence of a discrete spermine synthase enzyme that converts spermidine to spermine suggest that spermine must be needed and this is confirmed by studies with Gy mice and human patients with Snyder-Robinson syndrome in which spermine synthase is absent or greatly reduced. In both cases, this leads to a severe phenotype with multiple effects among which are intellectual disability, other neurological changes, hypotonia, and reduced growth of muscle and bone. This review describes these alterations and focuses on the roles of spermine which may contribute to these phenotypes including reducing damage due to reactive oxygen species, protection from stress, permitting correct current flow through inwardly rectifying K(+) channels, controlling activity of brain glutamate receptors involved in learning and memory, and affecting growth responses. Additional possibilities include acting as storage reservoir for maintaining appropriate levels of free spermidine and a possible non-catalytic role for spermine synthase protein.

NMDA and AMPA Receptors: Development and Status Epilepticus

Glutamate is the main excitatory neurotransmitter in the brain and ionotropic glutamate receptors mediate the majority of excitatory neurotransmission (Dingeldine et al. 1999). The high level of glutamatergic excitation allows the neonatal brain (the 2(nd) postnatal week in rat) to develop quickly but it also makes it highly prone to age-specific seizures that can cause lifelong neurological and cognitive disability (Haut et al. 2004). There are three types of ionotropic glutamate receptors (ligand-gated ion channels) named according to their prototypic agonists: N-methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) and kainate (KA). During early stages of postnatal development glutamate receptors of NMDA and AMPA type undergo intensive functional changes owing to modifications in their subunit composition (Carter et al. 1988, Watanabe et al. 1992, Monyer et al. 1994, Wenzel et al. 1997, Sun et al. 1998, Lilliu et al. 2001, Kumar et al. 2002, Matsuda et al. 2002, Wee et al. 2008, Henson et al. 2010, Pachernegg et al. 2012, Paoletti et al. 2013). Participation and role of these receptors in mechanisms of seizures and epilepsy became one of the main targets of intensive investigation (De Sarro et al. 2005, Di Maio et al. 2012, Rektor 2013). LiCl/Pilocarpine (LiCl/Pilo) induced status epilepticus is a model of severe seizures resulting in development temporal lobe epilepsy (TLE). This review will consider developmental changes and contribution of NMDA and AMPA receptors in LiCl/Pilo model of status epilepticus in immature rats.

The Effect of Cortical Spreading Depression on Glutamate Receptors in Rat Brain

E-mail: Fariba_karimzade@yahoo.com ABSTRACT Article info: Received: 25 Jun. 2013 Accepted: 23 Jul. 2013 هلاقم تاعلاطا 1392 ريت 4 :تفایرد 1392 دادرم 1 :شریذپ یمهم شقن هك دشاب یم یزكرم یبصع متسيس رد یتاذ یکيرتکلاويب تيلاعف کي هدنوشرشتنم راهم همدقم یراميب و ارذگ رشتنم یاه یشومارف ،عرص ،اروا اب نرگيم هلمج زا یکيژولورون یاه یراميب یژولويزيفوتاپ رد وراد قيرزت تهج( لوناك و هدش یحارج ناوجون یاه تر ادتبا هعلاطم نيا رد اه شور و داوم .دراد یعاخن یاه KCl قيرزت اب SD هورگ رد یرشق ي هدنوشرشتنم راهم .دندش هتشاك یزغم رشق یور تابث یاهدورتکلا و )اه هورگ لماش اه تر ی همه زغم .دش قيرزت رگنير لولحم ،مش هورگ رد .ديدرگ اقلا یلاوتم هتفه راهچ تدم هب اه هتفاي .ديدرگ ماجنا یميشوتسيهونوميا هعلاطم یارب یزاس هدامآ لحارم و هدش جراخ SD و مش ،لرتنك یاه شيازفا مش و لرتنك هورگ اب هسياقم رد SD هورگ رد یريگمشچ روط هب CA1 ی هيحان رد NR2B هدنريگ نايب هدهاشم SD هورگ رد CA3 و CA1 یحاون رد GluR1 ي هدنريگ نايب رد یراد ینعم شيازفا نينچمه .تفاي ي هدنريگ و NMDA یاه هدنريگ یاهدحاوريز زا NR2B هدنريگ نايب ،هدنوش رشتنم راهم یريگ هجيتن .ديدرگ .دهد یم شيازفا ناوجون یاه تر پمكوپيه فلتخم قطانم رد ار AMPA یاه هدنريگ یاهدحاو ريز زا GluR1

Effects of aging and low‐load balance exercise on the expression of neurotrophins and glutamate receptors in the mouse brain

The objective of this study was to investigate the effects of aging and low‐load balance exercise on the expression of neurotrophins and glutamate receptors in some brain regions including motor cortex, cerebellar cortex and hippocampus using senescence‐accelerated mice. The mice were assigned to four groups (adult‐control, adult‐exercise, aged‐control and aged‐exercise). The mice in the exercise groups performed balance exercise using a rotor rod (25 rpm, 15 min) three times a week for four weeks. The mRNA expression of neurotrophins, Trk receptors, and glutamate receptor subunits were measured based on real time PCR. All protocols were approved by the ethics committee for animal research of Saitama Prefectural University. Aging significantly decreased the expression of BDNF, TrkB, GluR2, NR1 and NR2B in the hippocampus. Aging also decreased the expression of BDNF, NT4 and NT3 in the cerebellar cortex. Exercise significantly increased the expression of TrkB, NR2A and NR2B only in the hippocampus of the aged mice to the expression level of the adult mice. This study elucidated the beneficial effects of the exercise on the expression of NMDA receptor and TrkB especially in the aged hippocampus, suggesting that low‐load and low‐frequency balance exercise has protective effects against degenerative disease in the aged hippocampus. This work was supported by JSPS KAKENHI Grant 21500471.

Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid

Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.