Glutamate And Gamma-amino Butyric Acid Research Articles

Thumbtack needle at front-mu points for abnormal behavior in children with autism spectrum disorders

To compare the clinical effect of thumbtack needle at front-mu points combined with conventional rehabilitation training and simple conventional rehabilitation training in the treatment of autism spectrum disorders (ASD). A total of 40 children with ASD were randomly divided into a combination group (20 cases, 3 cases dropped out) and a conventional rehabilitation group (20 cases, 3 cases dropped out). Conventional rehabilitation training i.e. language-cognition training and comprehensive education training was adopted in the conventional rehabilitation group, once a day, 5 days a week. On the basis of the treatment in the conventional rehabilitation group, thumbtack needle was applied at Zhongwan (CV 12), bilateral Tianshu (ST 25) and Guanyuan (CV 4) in the combination group, the needles were retained for 3 days each time, 3-day interval was taken between each treatment, for 5 times per month. One-month treatment was as one course and a total of 3 courses were required in both groups, with 10-day break between each course. Before and after treatment, the scores of autism behavior checklist (ABC), childhood autism rating scale (CARS), TCM spleen-stomach symptoms and Achenbach child behavior checklist (CBCL) were observed, and the serum ratio of glutamate and gamma-aminobutyric acid (Glu/GABA) was measured. After treatment, the scores of ABC, CARS and CBCL were decreased compared with those before treatment (P<0.05, P<0.01) in both groups, the TCM spleen-stomach symptoms score was decreased compared with that before treatment (P<0.05) in the combination group; the changes in the scores of ABC, CARS, TCM spleen-stomach symptoms and CBCL, as well as the serum Glu/GABA in the combination group were lager than those in the conventional rehabilitation group (P<0.05, P<0.01). Both thumbtack needle at front-mu points combined with conventional rehabilitation training and simple conventional rehabilitation training can effectively treat ASD, the combination treatment has superior effect on improving the abnormal behavior, spleen-stomach symptoms and balance of nerve impulse and inhibition.

Inhibition of mammillary body neurons by direct activation of Group II metabotropic glutamate receptors

The mammillary body is an important neural component of limbic circuitry implicated in learning and memory. Excitatory and inhibitory inputs, primarily mediated by glutamate and gamma-amino butyric acid (GABA), respectively, converge and integrate in this region, before sending information to the thalamus. One potentially overlooked mechanism for inhibition of mammillary body neurons is through direct activation of Group II metabotropic glutamate receptors (mGluRs). Here, whole-cell patch clamp recordings of in vitro slice preparations containing the mammillary body nuclei of the mouse were employed to record responses to bath application of pharmacological agents to isolate the direct effect of activating Group II mGluRs. Application of the Group II mGluR specific agonist, APDC, resulted in a hyperpolarization of the membrane potential in mammillary body neurons, likely resulting from the opening of a potassium conductance. These data suggest that glutamatergic inputs to the mammillary body may be attenuated via Group II mGluRs and implicates a functional role for these receptors in memory-related circuits and broadly throughout the central nervous system.

1H NMR-based metabonomics in brain nucleus accumbens and striatum following repeated cocaine treatment in rats

Studies have shown a few cerebral metabolites modified by cocaine in brain regions; however, endogenous metabolic profiling has been lacking. Ex vivo 1H NMR (hydrogen-1 nuclear magnetic resonance) spectroscopy-based metabonomic approach coupled with partial least squares was applied to investigate the changes of cerebral metabolites in nucleus accumbens (NAc) and striatum of rats subjected to cocaine treatment. Our results showed that both single and repeated cocaine treatment can induce significant changes in a couple of cerebral metabolites. The increase of neurotransmitters glutamate and gamma-amino butyric acid (GABA) were observed in NAc and striatum from the rats repeatedly treated with cocaine. Creatine and taurine increased in NAc whereas taurine increased and creatine decreased in striatum after repeated cocaine treatment. Elevation of N-acetylaspartate in NAc and striatum and decrease of lactate in striatum were observed, which may reflect the mitochondria dysregulation caused by cocaine; moreover, alterations of choline, phosphocholine and glycerol in NAc and striatum could be related to membrane disruption. Moreover, groups of rats with and without conditioned place preference (CPP) apparatus are presenting difference in metabolites. Collectively, our results provide the first evidence of metabonomic profiling of NAc and striatum in response to cocaine, exhibiting a regionally-specific alteration patterns. We find that repeated cocaine administration leads to significant metabolite alterations, which are involved in neurotransmitter disturbance, oxidative stress, mitochondria dysregulation and membrane disruption in brain.

The effect of mGlu8 deficiency in animal models of psychiatric diseases

The metabotropic glutamate receptor subtype 8 (mGlu(8)) is presynaptically located and regulates the release of the transmitter. Dysfunctions of this mechanism are involved in the pathophysiology of different psychiatric disorders. mGlu(8) deficient mice have been previously investigated in a range of studies, but the results are contradictory and there are still many open questions. Therefore, we tested mGlu(8)-deficient animals in different behavioral tasks that are commonly used in neuropsychiatric research. Our results show a robust contextual fear deficit in mGlu(8)-deficient mice. Furthermore, novel object recognition, chlordiazepoxide-facilitated extinction of operant conditioning and the acoustic startle response were attenuated by mGlu(8) deficiency. We found no changes in sensory processing, locomotor activity, prepulse inhibition, phencyclidine-induced changes in locomotion or prepulse inhibition, operant conditioning, conditioned fear to a discrete cue or in animal models of innate fear and post-traumatic stress disorder. We conclude that mGlu(8) might be a potential target for disorders with pathophysiological changes in brain areas where mGlu(8) modulates glutamate and gamma-amino butyric acid (GABA) transmission. Our data especially point to anxiety disorders involving exaggerated contextual fear, such as generalized anxiety disorders, and to conditions with disturbed declarative memory.

Dietary Taurine Supplementation Prevents Glial Alterations in Retina of Diabetic Rats

The preventive effect of dietary taurine supplementation on glial alterations in retina of streptozotocin-induced diabetic rats was examined in this study. Blood glucose content, content of taurine, glutamate and <gamma>-amino butyric acid (GABA) and expression of glial fibrillary acid protein (GFAP), vascular endothelial growth factor (VEGF), glutamate transporter (GLAST), glutamine synthetase (GS) and glutamate decarboxylase (GAD) in retina were determined in diabetic rats fed without or with 5% taurine in a controlled trial lasting 12 weeks, with normal rats fed without or with 5% taurine served as controls. Dietary taurine supplementation could not lower glucose concentration in blood (P > 0.05), but caused an elevation of taurine content and a decline in levels of glutamate and GABA in retina of diabetic rats (P < 0.05). The content of GABA in normal control group was not altered by taurine supplementation. With supplementation of taurine in diet, lower expression of GFAP and VEGF while higher expression of GLAST, GS and GAD in retina of diabetic rats were determinated by RT-PCR, Western-blotting and immunofluorescence (P < 0.05). GFAP, VEGF, GLAST, GS and GAD expressions in normal controls were not altered by taurine treatment. This may have prospective implications of using taurine to treat complications in diabetic retinopathy.

GABAergic circuitry in the opossum retina: a GABA release induced by l-aspartate

Glutamate and gamma-amino butyric acid (GABA) are the major excitatory and inhibitory neurotransmitters, respectively, in the central nervous system (CNS), including the retina. Although in a number of studies the retinal source of GABA was identified, in several species, as horizontal, amacrine cells and cells in the ganglion cell layer, nothing was described for the opossum retina. Thus, the first goal of this study was to determine the pattern of GABAergic cell expression in the South America opossum retina by using an immunohistochemical approach for GABA and for its synthetic enzyme, glutamic acid decarboxylase (GAD). GABA and GAD immunoreactivity showed a similar cellular pattern by appearing in a few faint horizontal cells, topic and displaced amacrine cells. In an effort to extend the knowledge of the opossum retinal circuitry, the possible influence of glutamatergic inputs in GABAergic cells was also studied. Retinas were stimulated with different glutamatergic agonists and aspartate (Asp), and the GABA remaining in the tissue was detected by immunohistochemical procedures. The exposure of retinas to NMDA and kainate resulted the reduction of the number of GABA immunoreactive topic and displaced amacrine cells. The Asp treatment also resulted in reduction of the number of GABA immunoreactive amacrine cells but, in contrast, the displaced amacrine cells were not affected. Finally, the Asp effect was totally blocked by MK-801. This result suggests that Asp could be indeed a putative neurotransmitter in this non-placental animal by acting on an amacrine cell sub-population of GABA-positive NMDA-sensitive cells.

Ethanol induces GAD67 and VGAT in slice cultures of newborn rat cerebral cortex

Exposure of the developing brain to ethanol disposes to the fetal alcohol syndrome, causing changes in the neurotransmitter systems of glutamate and gamma-amino butyric acid (GABA). However, expression of genes involved in GABA synthesis, vesicular and transmembrane transport has not been investigated so far. We exposed organotypic slice cultures of newborn rat cerebral cortex to ethanol (100 mM) for 4 days and observed a significant induction of the enzyme producing GABA (GAD67, +21%) and the vesicular transporter VGAT (+112%), whereas the expression of the transmembrane transporters did not differ from control conditions. In summary, ethanol exposure of the developing cortex induces GABAergic genes, which might facilitate the excitatory functions of GABA during development.

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments.

Glutamate and gamma-amino butyric acid (GABA) systems are emerging as targets for development of medications for mood disorders. There is increasing preclinical and clinical evidence that antidepressant drugs directly or indirectly reduce N-methyl-D-aspartate glutamate receptor function. Drugs that reduce glutamatergic activity or glutamate receptor-related signal transduction may also have antimanic effects. Recent studies employing magnetic resonance spectroscopy also suggest that unipolar, but not bipolar, depression is associated with reductions in cortical GABA levels. Antidepressant and mood-stabilizing treatments also appear to raise cortical GABA levels and to ameliorate GABA deficits in patients with mood disorders. The preponderance of available evidence suggests that glutamatergic and GABAergic modulation may be an important property of available antidepressant and mood-stabilizing agents. Future research will be needed to develop and evaluate new agents with specific glutamate and GABA receptor targets in the treatment of mood disorders.

Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain.

We review recent findings pertaining to several environmental agents (ethanol, phencyclidine, ketamine, nitrous oxide, barbiturates, benzodiazepines, halothane, isoflurane, and propofol) that have the potential to delete large numbers of neurons from the developing brain by a newly discovered mechanism involving interference in the action of neurotransmitters [glutamate and gamma-amino butyric acid (GABA) at (italic)N(/italic)-methyl-d-aspartate (NMDA)] and GABA(subscript)A(/subscript) receptors during the synaptogenesis period, also known as the brain growth-spurt period. Transient interference (lasting >= 4 hr) in the activity of these transmitters during the synaptogenesis period (the last trimester of pregnancy and the first several years after birth in humans) causes millions of developing neurons to commit suicide (die by apoptosis). Many of these agents are drugs of abuse (ethanol is a prime example) to which the human fetal brain may be exposed during the third trimester by drug-abusing mothers. Ethanol triggers massive apoptotic neurodegeneration in the developing brain by interfering with both the NMDA and GABA(subscript)A(/subscript) receptor systems, and this can explain the reduced brain mass and lifelong neurobehavioral disturbances associated with intrauterine exposure of the human fetus to ethanol (fetal alcohol syndrome). Exposure of the immature brain in a medical treatment context is also of concern because many of these agents are drugs used frequently as sedatives, tranquilizers, anticonvulsants, or anesthetics in pediatric and/or obstetrical medicine. Because this is a newly discovered mechanism, further research will be required to fully ascertain the nature and degree of risk posed by exposure of the developing human brain to environmental agents that act by this mechanism.

Region-specific localization of glutamine synthetase immunoreactivity in the mouse olfactory bulb: implications for neuron-glia interaction in bulbar synaptic plasticity.

Glutamine synthetase (GS) critically regulates the metabolism of glutamate and gamma-amino butyric acid (GABA), which mediate synaptic plasticity in the olfactory bulb. In this study, GS immunolocalization in the mouse olfactory bulb was examined. The main and accessory subdivisions of the olfactory bulb possess GS-positive cells and processes in the plexiform-, the mitral- and the granule cell layers. GS has been demonstrated to show a predominantly astrocytic localization; its presence in the cell layers implicated in glutamatergic and GABAergic function therefore suggests that bulbar synaptic plasticity in mice may be regulated by astroglia and, together with other lines of evidence, point to the possibility of a functional astroglia-neuron system in the mouse olfactory bulb.

Neural integrative activities of nucleus accumbens subregions in relation to learning and motivation

In recent years, there has been much interest in the functional specializations of nucleus accumbens subregions. The two zones within the nucleus accumbens that have received considerable attention are the accumbens core, consisting of ventral striatal tissue surrounding the anterior commissure, and the accumbens shell, which envelops the core on its medial, ventral, and lateral borders. Differential connectivity and histochemical profiles suggest that these two subterritories may have distinctive behavioral roles with regard to the regulation of motivated behavior. Experiments focusing primarily on amino acid–coded neurotransmitter systems in these regions—that is, glutamate and gamma-amino butyric acid (GABA)—have revealed specific and contrasting functions of the core and the shell. It is proposed that the accumbens core, and specifically N-methyl-d-aspartate receptor-dependent plasticity within this area, is part of a network critical for appetitive instrumental learning, in which a motor response becomes “stamped in” when followed by a rewarding stimulus or event. The accumbens shell, particularly GABA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors within the shell, is implicated in the executive control of brain feeding circuits and may also represent a key area at which appetitive and aversive stimuli interact to control behavioral selection. These functional specializations within the nucleus accumbens subregions may be integrated through the coordination of activity within striatal neuronal ensembles that communicate with complex networks of limbic, thalamic, and prefrontal circuitry.

Intra-striatal phencyclidine inhibits n-methyl-d-aspartic acid-stimulated increase in glutamate levels of freely moving rats

1. 1. The authors investigated the effect of local phencyclidine (phenylcyclohexylpiperidine, PCP) on extracellular levels of glutamate and gamma-amino butyric acid (GABA) in rat striatum using in vivo microdialysis. 2. 2. Intrastriatal infusion of PCP (1 mM) via a microdialysis probe did not alter the basal extracellular levels of either glutamate or GABA. Addition of N-methyl-D-aspartic acid (NMDA; 0. 2, 0. 5 and 1 mM) to the perfusion medium resulted in a dose-dependent increase in extracellular levels of glutamate. 3. 3. Intrastriatal infusion of tetrodotoxin (0. 1, 1, 10 μM), a highly selective blocker of voltage-dependent sodium channels, significantly attenuated the NMDA-stimulated release of glutamate, suggesting that NMDA-evoked release of glutamate originated from the neuronal pool and that the increase of striatal glutamate level was regulated indirectly via NMDA receptors. 4. 4. The NMDA-induced release of glutamate was reduced significantly by pretreatment with local PCP(1 mM). Dizocilpine (MK801; 0. 2 mM), a non-competitive NMDA antagonist, completely inhibited the NMDA-stimulated release of glutamate. 5. 5. These results suggest that, in the striatum, PCP inhibits corticostriatal glutamatergic neuro-transmission by inhibiting the release of glutamate probably via postsynaptic NMDA receptors.

Interrelationship between differentiation and malignancy-associated properties in glioma

The phenotypic expression of cells derived from human anaplastic astrocytomas, rat glioma, normal human adult and foetal brain tissue have been examined for differentiated and malignancy-associated properties. Glial fibrillary acidic protein (GFAP), high affinity glutamate and gamma-amino butyric acid (GABA) uptake and glutamine synthetase were used as indicators of astroglial differentiation. Plasminogen activator and tumour angiogenesis factor were the malignancy-associated markers. The normal adult brain-derived lines showed some differentiated astroglial features and expressed low levels of the malignancy-associated properties. The foetal cultures contained highly differentiated astroglia while the glioma lines showed considerable phenotypic heterogeneity from highly differentiated to undifferentiated. The least differentiated glioma cells exhibited the highest plasminogen activator activities. The density-dependent control of phenotypic expression was also investigated. High affinity GABA uptake, and GFAP in rat C6 glioma cultures, increased with increasing monolayer cell density, events probably mediated by an increase in the formation of cell-cell contacts at confluence. Plasminogen activator activity decreased with increasing cell density.