Glutamate neurotoxicity in cortical cell culture

TLDR

Glutamate neurotoxicity is implicated in neuronal loss across several neurological diseases, yet studying it in intact systems remains challenging. This study investigates glutamate neurotoxicity with high precision in dissociated fetal mouse neocortex cultures. The authors used dissociated fetal mouse neocortex cultures to examine glutamate‑induced neuronal damage. Brief glutamate exposure rapidly induces morphological changes and subsequent degeneration in mature cortical neurons (ED50 50–100 µM for 5 min), while immature neurons and glia remain resistant, uptake is not limiting, glutamate proves more potent than kainate, and a subset of neurons survives with similar electrophysiological properties.

Abstract

The central neurotoxicity of the excitatory amino acid neurotransmitter glutamate has been postulated to participate in the pathogenesis of the neuronal cell loss associated with several neurological disease states, but the complexity of the intact nervous system has impeded detailed analysis of the phenomenon. In the present study, glutamate neurotoxicity was studied with novel precision in dissociated cell cultures prepared from the fetal mouse neocortex. Brief exposure to glutamate was found to produce morphological changes in mature cortical neurons beginning as quickly as 90 sec after exposure, followed by widespread neuronal degeneration over the next hours. Quantitative dose- toxicity study suggested an ED50 of 50–100 microM for a 5 min exposure to glutamate. Immature cortical neurons and glia were not injured by such exposures to glutamate. Uptake processes probably do not limit GNT in culture, as the uptake inhibitor dihydrokainate did not potentiate GNT. Possibly reflecting the lack of uptake limitation, glutamate was found to be actually more potent than kainate as a neurotoxin in these cultures, a dramatic reversal of the in vivo potency rank order. Some neurons regularly survived brief glutamate exposure; these possibly glutamate-resistant neurons had electrophysiologic properties, including chemosensitivity to glutamate, that were grossly similar to those of the original population.