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Cerebral Cortex Advance Access published online on October 26, 2007
Cerebral Cortex, doi:10.1093/cercor/bhm165
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© The Author 2007. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Activity-Dependent Regulation of Neuronal Apoptosis in Neonatal Mouse Cerebral Cortex

Nicolas Heck1, Antje Golbs1, Therese Riedemann1, Jyh-Jang Sun1, Volkmar Lessmann1,2 and Heiko J. Luhmann1

1 Institute of Physiology and Pathophysiology, University of Mainz, Duesbergweg 6, D-55128 Mainz, Germany, 2 Current address: Volkmar Lessmann Institute of Physiology, Otto-von-Guericke-University, 39120 Magdeburg, Germany

Address correspondence to email: luhmann{at}uni-mainz.de.

A massive neuronal loss during early postnatal development has been well documented in the murine cerebral cortex, but the factors that drive cells into apoptosis are largely unknown. The role of neuronal activity in developmental apoptosis was studied in organotypic neocortical slice cultures of newborn mice. Multielectrode array and whole-cell patch-clamp recordings revealed spontaneous network activity characterized by synchronized burst discharges, which could be blocked by tetrodotoxin and ionotropic glutamate receptor antagonists. The identical neuropharmacological manipulations also caused a significant increase in the number of apoptotic neurons as early as 6 h after the start of drug treatment. Moreover, inhibition of the NMDA receptor subunit NR2A or NR2B induced a differential short-term versus delayed increase in the apoptosis rate, respectively. Activation of L-type, voltage-dependent calcium channels was neuroprotective and could prevent activity-dependent apoptosis during NMDA receptor blockade. Furthermore, this effect involved phosphorylation of cAMP response element–binding protein and activation of the tropomyosin-related kinase (Trk) receptors. Inhibition of electrical synapses and blockade of ionotropic {gamma}-aminobutyric acid receptors induced specific changes in spontaneous electrical activity patterns, which caused an increase in caspase-3–dependent cell death. Our results demonstrate that synchronized spontaneous network bursts activating ionotropic glutamate receptors promote neuronal survival in the neonatal mouse cerebral cortex.

Key Words: apoptosis • cell death • development • neocortex • NMDA • spontaneous activity


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