Glutamate In Central Nervous System Research Articles

This Month in the Journal

This Month in the Journal

Chapter 4 Physiological and pathological operation of glutamate transporters

Publisher Summary This chapter describes the recent advancement in understanding the properties and functional role of central nervous system glutamate transporters and focuses on the properties of an anion channel present in the transporters, the existence of postsynaptic glutamate uptake, recent controversy over the ionic stoichiometry of glutamate transport, the role of glutamate transporters in raising the extracellular glutamate concentration in brain ischaemia, and the possible importance of glutamate transporters other than the sodium-dependent carriers. However, in pathological conditions, such as brain ischaemia, when there is a run-down of the ionic gradients, which power glutamate uptake, the carriers may run backwards, releasing glutamate into the extracellular space, and thus triggering the death of neurons. Glutamate uptake can be monitored as an inward membrane current in part because of the cotransport of ions, which power the movement of glutamate. Radiotracing experiments, showing that most radioactive glutamate applied to brain tissue ends up in glial cells, suggest that glial cells have more glutamate transporters than neurons.

Activation and Involvement of p38 Mitogen-activated Protein Kinase in Glutamate-induced Apoptosis in Rat Cerebellar Granule Cells

In the mammalian central nervous system glutamate is the major excitatory neurotransmitter and plays a crucial role in plasticity and toxicity of certain neural cells. We found that glutamate stimulated activation of p38 and stress-activated protein kinase (SAPK, also known as c-Jun N-terminal kinase (JNK)), two subgroup members of the mitogen-activated protein kinase superfamily in matured cerebellar granule cells. The p38 activation was largely mediated by N-methyl-D-aspartate receptors. Furthermore, we have revealed a novel signaling pathway, that is, Ca2+-mediated activation of p38 in glutamate-treated granule cells. The glutamate concentration effective for inducing apoptosis correlated with that for inducing p38 activation. SB203580, a specific inhibitor for p38, inhibited glutamate-induced apoptosis. Thus p38 might be involved in glutamate-induced apoptosis in cerebellar granule cells.

NMDA-like receptors in the CNS of molluscs

The properties of L-glutamate sensitive neurones in the fresh-water snail Lymnaea stagnalis were studied to determine whether or not NMDA type receptors are present in molluscan ganglia. Experiments were carried out in isolated ganglia and with dialysed neurones. In the neuro-secretory light yellow cells (LYC) both glutamate and NMDA (but not other glutamate agonists) induced prolonged depolarization and inward current. The sensitivity of the neurones for NMDA was lower than for glutamate. Both currents are carried by Na- and Ca-ions and have linear I-V characteristics. Mg-ions did not reduce either but glycine potentiated both glutamate and NMDA responses. It is concluded that in the molluscan central nervous system glutamate receptors have some of the characteristics of mammalian NMDA receptors.

Brain glutamate metabolism during metabolic alkalosis and acidosis.

Glutamate modifies ventilation by altering neural excitability centrally. Metabolic acid-base perturbations may also alter cerebral glutamate metabolism locally and thus affect ventilation. Therefore, the effect of metabolic acid-base perturbations on central nervous system glutamate metabolism was studied in pentobarbital-anesthetized dogs under normal acid-base conditions and during isocapnic metabolic alkalosis and acidosis. Cerebrospinal fluid transfer rates of radiotracer [13N]ammonia and of [13N]glutamine synthesized de novo via the reaction glutamate+NH3-->glutamine in brain glia were measured during normal acid-base conditions and after 90 min of acute isocapnic metabolic alkalosis and acidosis. Cerebrospinal fluid [13N]ammonia and [13N]glutamine transfer rates decreased in metabolic acidosis. Maximal glial glutamine efflux rate jm equals 85.6 +/- 9.5 (SE) mumol.l-1 x min-1 in all animals. No difference in jm was observed in metabolic alkalosis or acidosis. Mean cerebral cortical glutamate concentration was significantly lower in acidosis [7.01 +/- 0.45 (SE) mumol/g brain tissue] and tended to be larger in alkalosis, compared with 7.97 +/- 0.89 mumol/g in normal acid-base conditions. There was a similar change in cerebral cortical gamma-aminobutyric acid concentration. Within the limits of the present method and measurements, the results suggest that acute metabolic acidosis but not alkalosis reduces glial glutamine efflux, corresponding to changes in cerebral cortical glutamate metabolism. These results suggest that glutamatergic mechanisms may contribute to central respiratory control in metabolic acidosis.

Brain glutamate metabolism during hypoxia and peripheral chemodenervation

Glutamate stimulates resting ventilation by altering neural excitability centrally. Hypoxia increases central ventilatory drive through peripheral chemoreceptor stimulation and may also alter cerebral perfusion and glutamate metabolism locally. Therefore the effect of hypoxia and peripheral chemodenervation on cerebrospinal fluid (CSF) transfer rate of in vivo tracer amidated central nervous system glutamate was studied in intact and chemodenervated pentobarbital-anesthetized dogs during normoxia and after 1 h of hypoxia induced with 10 or 12% O2 in N2 breathing at constant expired ventilation and arterial CO2 tension. Chemodenervation was performed by bilateral sectioning of the carotid body nerves and cervical vagi. CSF transfer rates of radiotracer 13NH4+ and [13N]glutamine synthesized via the reaction, glutamate + NH4(+)----glutamine, in brain glia were measured during normoxia and after 1 h of hypoxia. At normoxia, maximal glial glutamine efflux rate jm = 103.3 +/- 11.2 (SE) mumol.l-1.min-1 in all animals. After 1 h of hypoxia in intact animals, jm = 78.4 +/- 10.0 mumol.l-1.min-1. In denervated animals, jm was decreased to 46.3 +/- 4.3 mumol.l-1.min-1. During hypoxia, mean cerebral cortical glutamate concentration was higher in denervated animals (9.98 +/- 1.43 mumol/g brain tissue) than in intact animals (7.63 +/- 1.82 mumol/g brain tissue) and corresponding medullary glutamate concentration tended to be higher in denervated animals. There were no differences between mean glutamine and gamma-aminobutyric acid concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)