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The Journal of Neuroscience, December 1, 2000, 20(23):8831-8837

NMDA and Glutamate Evoke Excitotoxicity at Distinct Cellular Locations in Rat Cortical Neurons In Vitro

Jeroo D. Sinor¹, Shen Du¹, Sriram Venneti¹, Rachel C. Blitzblau², Daniel N. Leszkiewicz¹, Paul A. Rosenberg², and Elias Aizenman¹

¹ Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, and ² Department of Neurology and Program in Neuroscience, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115

The development of cortical neurons in vivo and in vitro is accompanied by alterations in NMDA receptor subunit expression and concomitant modifications in the pharmacological profile of NMDA-activated ionic currents. For example, we observed that with decreasing NR2B/NR2A subunit expression ratio, the block of NMDA receptor-mediated whole-cell responses by the NR2B-selective antagonist haloperidol was also decreased. In mature cultures (>22 d in vitro), however, NMDA responses obtained from excised nucleated macropatches, which comprised a large portion of the soma, remained strongly antagonized by haloperidol. These results suggest that in more mature neurons NR1/NR2B receptors appear to be preferentially expressed in the cell body. As predicted from the whole-cell recording pharmacological profile, NMDA-induced toxicity was largely unaffected by haloperidol in mature cultures. However, haloperidol effectively blocked glutamate toxicity in the same cultures, suggesting that the neurotoxic actions of this amino acid were mostly due to the activation of somatic NMDA receptors. In experiments in which the potency of glutamate toxicity was increased by the transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid, the neuroprotective effects of haloperidol were significantly diminished. This was likely because of the fact that glutamate, now toxic at much lower concentrations, was able to reach and activate dendritic receptors under these conditions. These results strongly argue that exogenous glutamate and NMDA normally induce excitotoxicity at distinct cellular locations in mature mixed neuronal cultures and that NR1/NR2B receptors remain an important component in the expression of glutamate, but not NMDA-induced excitotoxicity.

Key words: haloperidol; development; excitotoxicity; NMDA receptors; glutamate; NR2B subunit; glutamate transport; cortical neurons; tissue culture

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20238831-07$05.00/0

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