Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation
Article first published online: 14 MAR 2002
Journal of Neurochemistry
Volume 80, Issue 4, pages 589–597, February 2002
How to Cite
Hashimoto, R., Hough, C., Nakazawa, T., Yamamoto, T. and Chuang, D.-M. (2002), Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. Journal of Neurochemistry, 80: 589–597. doi: 10.1046/j.0022-3042.2001.00728.x
- Issue published online: 14 MAR 2002
- Article first published online: 14 MAR 2002
- Received October 4, 2001; revised manuscript received November 8, 2001; accepted November 9, 2001.
- bipolar disorder;
- NMDA receptor;
The therapeutic mechanisms of lithium for treating bipolar mood disorder remain poorly understood. Recent studies demonstrate that lithium has neuroprotective actions against a variety of insults. Here, we studied neuroprotective effects of lithium against excitotoxicity in cultured cerebral cortical neurons. Glutamate-induced excitotoxicity in cortical neurons was exclusively mediated by NMDA receptors. Pre-treatment of cortical neurons with LiCl time-dependently suppressed excitotoxicity with maximal protection after 6 days of pre-treatment. Significant protection was observed at the therapeutic and subtherapeutic concentration of 0.2–1.6 mm LiCl with almost complete protection at 1 mm. Neuroprotection was␣also elicited by valproate, another major mood-stabilizer. The neuroprotective effects of lithium coincided with inhibition␣of␣NMDA receptor-mediated calcium influx. Lithium pre-treatment did not alter total protein levels of NR1, NR2A and NR2B subunits of NMDA receptors. However, it did markedly reduce the level of NR2B phosphorylation at Tyr1472 and this was temporally associated with its neuroprotective effect. Because NR2B tyrosine phosphorylation has been positively correlated with NMDA receptor-mediated synaptic activity and excitotoxicity, the suppression of NR2B phosphorylation by lithium is likely to result in the inactivation of NMDA receptors and contributes to neuroprotection against excitotoxicity. This action could also be relevant to its clinical efficacy for bipolar patients.