Degeneration of cultured cortical neurons following prolonged inactivation: molecular mechanisms
Article first published online: 5 JUN 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 110, Issue 4, pages 1203–1213, August 2009
How to Cite
Schonfeld-Dado, E., Fishbein, I. and Segal, M. (2009), Degeneration of cultured cortical neurons following prolonged inactivation: molecular mechanisms. Journal of Neurochemistry, 110: 1203–1213. doi: 10.1111/j.1471-4159.2009.06204.x
- Issue published online: 21 JUL 2009
- Article first published online: 5 JUN 2009
- Received February 2, 2009; revised manuscript received April 30, 2009; accepted May 28, 2009.
- cortical neurons;
Networks of neurons express persistent spontaneous network activity when maintained in dissociated cultures. Prolonged blockade of the spontaneous activity with tetrodotoxin (TTX) causes the eventual death of the neurons. In this study, we investigated some molecular mechanisms that may underlie the activity-suppressed slow degeneration of cortical neurons in culture. Already after 3–4 days of exposure to TTX, well before the neurons die, they began to express markers that lead to their eventual death, 7–10 days later. There was a reduction in glutamate receptor (GluR2) expression, a persistent increase in intracellular calcium concentration, activation of calpain, and an increase in spectrin breakdown products. At this point, blockade of GluR2-lacking GluR1 or calpain (either with a selective antagonist or through the natural regulator of calpain, calpastatin), protected cells from the toxic action of TTX. Subsequently, mitochondria lost their normal elongated shape as well as their membrane potential. Eventually, neurons activated caspase 3 and PUMA (p53 up-regulated modulator of apoptosis), hallmarks of neuronal apoptosis, and died. These experiments will lead to a better understanding of slow neuronal death, typical of neurodegenerative diseases.