NMDA and non-NMDA receptor-mediated excitotoxicity are potentiated in cultured striatal neurons by prior chronic depolarization

The excitatory input from cortex and/or thalamus to striatum appears to pro mote the maturation of glutamate receptors on striatal neurons, but the mec hanisms by which it does so have been uncertain. To explore the possibility that the excitatory input to striatum might influence glutamate receptor m aturation on striatal neurons, at least in part, by its depolarizing effect on striatal neurons, we examined the influence of chronic KCl depolarizati on on the development of glutamate receptor-mediated excitotoxic vulnerabil ity and glutamate receptors in cultured striatal neurons. Dissociated stria tal neurons from E17 rat embryos were cultured for 2 weeks in Barrett's med ium containing either low (3 mM) or high (25 mM) KCl. The vulnerability of these neurons to NMDA receptor agonists (NMDA and quinolinic acid), non-NMD A receptor agonists (AMPA and KA), and a metabotropic glutamate receptor ag onist (trans-ACPD) was examined by monitoring cell loss 24 h after a 1-h ag onist exposure. We found that high-KCl rearing potentiated the cell loss ob served with 500 mu M NMDA or 250 mu M KA and yielded cell loss with 250 mu M AMPA that was not evident under low KCl rearing. In contrast, neither QA up to 5 mM nor trans-ACPD had a significant toxic effect in either KCl grou p. ELISA revealed that chronic high KCI doubled the abundance of NMDA NR2A/ B, AMPA GluR2/3, and KA GluR5-7 receptor subunits on cultured striatal neur ons and more than doubled AMPA GluR1 and GluR4 subunits, but had no effect on NMDA NR1 subunit levels. These receptor changes may contribute to the po tentiation of NMDA and non-NMDA receptor-mediated excitotoxicity shown by t hese neurons following chronic high-KCl rearing. Our studies suggest that m embrane depolarization produced by corticostriatal and/or thalamostriatal i nnervation may be required for maturation of glutamate receptors on striata l neurons, and such maturation may be important for expression of NMDA and non-NMDA receptor-mediated excitotoxicity by striatal neurons. Striatal cul tures raised under chronically depolarized conditions may, thus, provide a more appropriate culture model to study the role of NMDA or non-NMDA recept or subtypes in excitotoxicity in striatum, a 1999 Academic Press.