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The Journal of Neuroscience, June 15, 2003, 23(12):4942-4950
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Chloride Influx Aggravates Ca2+-Dependent AMPA Receptor-Mediated Motoneuron Death
P. Van Damme,1
G. Callewaert,2
J. Eggermont,2
W. Robberecht,1 and
L. Van Den Bosch1
Departments of 1Neurobiology and 2Physiology, Catholic University Leuven, Campus Gasthuisberg, B-3000 Leuven, Belgium
AMPA receptor-mediated excitotoxicity has been implicated in the pathogenesis of stroke, neurotrauma, epilepsy, and many neurodegenerative diseases such as motoneuron disease. We studied the role of Cl- in AMPA receptor-mediated Ca2+-dependent excitotoxicity in cultured rat spinal motoneurons. Using the gramicidin perforated patch-clamp technique, the intracellular Cl- concentration could be calculated from the reversal potential of the GABA-induced current. The membrane depolarization caused by AMPA receptor stimulation resulted in Cl- influx through 5-nitro-2(3-phenylpropyl-amino) benzoic acid- and niflumic acid-sensitive Cl- channels. Cl- influx during AMPA receptor stimulation aggravated excitotoxic motoneuron death by two mechanisms: an increase of AMPA receptor conductance and an elevation of the Ca2+ driving force through a partial repolarization. The Cl- influx during AMPA receptor stimulation was enhanced by coadministration of GABA. This resulted in an increased Ca2+ influx and an enhanced cell death, suggesting that concomitant GABAergic stimulation may aggravate excitotoxic motoneuron death.
Key words: AMPA receptor; calcium; motoneuron; chloride; excitotoxicity; amyotrophic lateral sclerosis
Received Oct. 16, 2002;
revised Apr. 8, 2003;
accepted Apr. 8, 2003.
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