Glial uptake of excitatory amino acids influences neuronal survival in cultures of mouse hippocampus

Sugiyama, Kohachiro; Brunori, A.; Mayer, Mark L.

doi:10.1016/0306-4522(89)90298-4

Cited by 93 publications

(39 citation statements)

References 25 publications

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“…However, while elevated glutamate is lethal, previous studies in the cerebellum (7)(8)(9) Maintaining glutamate concentrations within this trophic window may be an important in vivo role for astrocytes. Astrocytes are known to accumulate glutamate and convert it to the inactive amino acid glutamine, thus protecting neurons from the excitotoxic effects of high glutamate (36,37). Recently, cultured rat hippocampal astrocytes have also been shown to be capable of releasing glutamate by a Ca2+-dependent mechanism (30).…”

Section: Resultsmentioning

confidence: 99%

Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse.

Bambrick

Yarowsky

Krueger

1995

Proc. Natl. Acad. Sci. U.S.A.

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The survival of cultured mouse hippocampal neurons was found to be greatly enhanced by micromolar concentrations of the excitatory neurotransmitter glutamate.Blockade of kainate/AMPA (c-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptors increased the rate of neuron death, suggesting that endogenous glutamate in the cultures promotes survival. Addition of glutamate (0.5-1 ,uM) further increased neuron survival, whereas glutamate in excess of20 ,iM resulted in increased death. Thus, the survival vs. glutamate dose-response relation is bell-shaped with an optimal glutamate concentration near 1 IzM. We found that hippocampal neurons from mice with the genetic defect trisomy 16 (Ts16) died 2-3 times faster than normal (euploid) neurons. Moreover, glutamate, at all concentrations tested, failed to increase survival of Ts16 neurons. In contrast, the neurotrophic polypeptide basic fibroblast growth factor did increase the survival of Ts16 and euploid neurons. Ts16 is a naturally occurring mouse genetic abnormality, the human analog of which (Down syndrome) leads to altered brain development and Alzheimer disease. These results demonstrate that the Ts16 genotype confers a defect in the glutamate-mediated survival response ofhippocampal neurons and that this defect can contribute to their accelerated death.The virtual absence of neurogenesis in the adult mammalian brain underscores the necessity of ensuring the survival of neurons over many years. Since it has been suggested that all cells require a constant trophic signal to block cell death (1), the loss of neurons associated with normal aging and the accelerated neuronal death characteristic of neurodegenerative disorders could result from the failure of one or more intrinsic survival mechanisms.Many agents have been shown to promote the survival of neurons. Polypeptide neurotrophic factors (2-5) include basic fibroblast growth factor (bFGF), glial cell line-derived neurotrophic factor, and the neurotrophins-e.g., nerve growth factor and brain-derived neurotrophic factor. Not all types of neurons respond to every neurotrophic factor, but many neurons respond to multiple factors, providing a redundancy of trophic inputs to ensure long-term neuron survival. Activation of excitatory amino acid receptors has also been shown to elicit a trophic response in neurons. Although very high concentrations of glutamate are toxic to most neurons (for review, see ref. 6), lower concentrations of glutamate or glutamate agonists have been reported to increase survival of postnatal cerebellar granule cells in vitro (7-9), while glutamate receptor (GluR) antagonists can decrease their survival (7). Similarly, metabotropic GluR activation has been found to promote the in vitro survival of cerebellar Purkinje and granule cells (10, 11). It has also been shown that in vivo treatment with N-methyl-D-aspartate (NMDA) GluR antagonists decreases the numbers of surviving granule cells in the developing dentate gyrus of the hippocampus (12), suggesting that endogenou...

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Section: Resultsmentioning

confidence: 99%

Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse.

Bambrick

Yarowsky

Krueger

1995

Proc. Natl. Acad. Sci. U.S.A.

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“…A likely reason for this discrepancy is that our culture methods have changed markedly and we now use media with much extracellular GLU and aspartate. This makes less serum and much lower neurons less sensitive to GLU (Sugiyama et al, 1989;Erdo et al, 1990). Our neurons are still killed by GLU, but the lethal concentration has increased.…”

Section: Discussionmentioning

confidence: 96%

Intracellular calcium concentrations during "chemical hypoxia" and excitotoxic neuronal injury

1991

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Because hypoxic/ischemic neurodegeneration appears to be in part linked to glutamate neurotoxicity, we measured intracellular calcium (Ca2+i) levels in cultured hippocampal neurons during exposure to toxic doses of glutamate (GLU) and to an anoxic environment simulated by sodium cyanide (NaCN). Changes in Ca2+i produced by cyanide greatly exceeded those induced by GLU. The NaCN response was mimicked when oxidative metabolism was also disrupted by sodium azide, oligomycin, or dinitrophenol. Noncompetitive NMDA receptor antagonists and enzymatic GLU degradation abolished the GLU-induced Ca2+i increases and attenuated those produced by NaCN. Only NaCN-induced increases were blocked when dantrolene and ruthenium red were applied to prevent release from intracellular pools. All responses were reduced proportionally in the absence of added external calcium. These results suggest that extracellular GLU accumulation and subsequent activation of GLU receptors were involved in the NaCN response. During such metabolic compromise, however, GLU-induced elevations of Ca2+i were enormously amplified. In parallel toxicity studies, NaCN was not neurotoxic despite the large elevations in Ca2+i, indicating that a general elevation in cytoplasmic calcium does not necessarily predict neurodegeneration.

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“…Thus one key mechanism by which increased astrocyte glycogen stores may improve neuronal survival under these conditions is by fueling contin ued uptake of released aspartate and glutamate (Sugiyama et al, 1989); astrocyte membrane pumps might also help keep local K + concentration down, reducing neuronal excitability. Although the medium volume is very large relative to the cell vol ume, Harris et al (1989) have shown that neuronal processes and synapses in cortical cultures can be sequestered by glial membranes.…”

Section: Discussionmentioning

confidence: 99%

Glial Glycogen Stores Affect Neuronal Survival during Glucose Deprivation in vitro

Swanson

Choi

1993

J Cereb Blood Flow Metab

225

155

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Summary: Glia perform several energy-dependent func tions that may aid neuronal survival under pathological conditions. Glycogen is the major energy reserve in brain, and it is localized almost exclusively to astrocytes. Using murine cortical cell cultures containing both glia and neu rons, we examined the effect of altered glial glycogen stores on neuronal survival following glucose depriva tion. As previously reported, cultures exposed for several hours to media lacking glucose developed widespread neuronal degeneration without glial degeneration. If glial astrocyte glycogen content was increased to 2-3 times Astrocytes perform multiple functions essential for the normal activity of neurons in the brain. In addition to providing mechanical support and trophic factors (Bunge and Waksman, 1985), astro cytes maintain homeostasis of the brain extracellu lar fluid (ECF). Astrocytes are largely responsible for the uptake and catabolism of excitatory amino acids and other neurotransmitters (Ericinska et aI., 1986;Hertz, 1979;Varon and Somjen, 1979), and for the uptake and redistribution of K + (Hertz, 198 1; Jendelova and Sykova, 199 1). Astrocytic am monia fixation provides the only mechanism other than diffusion for clearing brain ammonia (Cooper and Lai, 1987). Astrocytes may also play an impor-

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Glial uptake of excitatory amino acids influences neuronal survival in cultures of mouse hippocampus

Cited by 93 publications

References 25 publications

Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse.

Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse.

Intracellular calcium concentrations during "chemical hypoxia" and excitotoxic neuronal injury

Glial Glycogen Stores Affect Neuronal Survival during Glucose Deprivation in vitro

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