Characterization of glutamate toxicity in cultured rat cerebellar granule neurons at reduced temperature

Frederick W. Berman, Thomas F. Murray

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

We have defined conditions whereby glutamate becomes toxic to isolated cerebellar granule neurons in a physiologic salt solution (pH 7.4). In the presence of a physiologic Mg++ concentration, acute glutamate excitotoxicity manifests only when the temperature was reduced from 37°C to 22°C. In contrast to glutamate, N-methyl-D-aspartate (NMDA) was non-toxic at either temperature at concentrations as high as 1 mM. Glycine strongly potentiated both the potency and efficacy of glutamate but revealed only a modest NMDA response. The non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxalinedione (CNQX), potently protected against glutamate challenge, although the contribution of antagonism at strychnine-insensitive glycine sites could not be excluded. To further characterize the non-NMDA receptor contribution to the excitotoxic response, the promiscuity of glutamate interaction with ionotropic receptors was simulated by exposing neurons to NMDA in the presence of non-NMDA receptor agonists. NMDA toxicity was potentiated four- to sevenfold when non-NMDA receptors were coactivated by a subtoxic concentration of AMPA, kainate, or domoate. These results suggest that non-NMDA receptor activation participates in the mechanism of acute glutamate toxicity by producing neuronal depolarization (via sodium influx), which in turn promotes the release of the voltage-dependent magnesium blockade of NMDA receptor ion channels.

Original languageEnglish
Pages (from-to)111-119
Number of pages9
JournalJournal of Biochemical Toxicology
Volume11
Issue number3
StatePublished - 1996
Externally publishedYes

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D-Aspartic Acid
Neurons
Toxicity
Rats
Glutamic Acid
N-Methylaspartate
Temperature
Glycine
Strychnine
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Kainic Acid
Poisons
Depolarization
N-Methyl-D-Aspartate Receptors
Ion Channels
Magnesium
Salts
Sodium
Chemical activation
aspartic acid receptor

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Characterization of glutamate toxicity in cultured rat cerebellar granule neurons at reduced temperature. / Berman, Frederick W.; Murray, Thomas F.

In: Journal of Biochemical Toxicology, Vol. 11, No. 3, 1996, p. 111-119.

Research output: Contribution to journalArticle

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