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The Journal of Neuroscience, January 1, 2000, 20(1):240-250
AMPA Exposures Induce Mitochondrial Ca2+ Overload and
ROS Generation in Spinal Motor Neurons In Vitro
Sean G.
Carriedo3,
Stefano L.
Sensi1,
Hong Z.
Yin1, and
John H.
Weiss1, 2, 3
Departments of 1 Neurology, 2 Anatomy and
Neurobiology, and 3 Neurobiology and Behavior, University
of California, Irvine, Irvine, California 92697-4292
The reason for the selective vulnerability of motor neurons in
amyotrophic lateral sclerosis (ALS) is primarily unknown. A possible
factor is the expression by motor neurons of
Ca2+-permeable AMPA/kainate channels, which
may permit rapid Ca2+ influx in response to synaptic
receptor activation. However, other subpopulations of central neurons,
most notably forebrain GABAergic interneurons, consistently express
large numbers of these channels but do not degenerate in ALS. Indeed,
when subjected to identical excitotoxic exposures, motor neurons were
more susceptible than GABAergic neurons to AMPA/kainate
receptor-mediated neurotoxicity. Microfluorimetric studies were
performed to examine the basis for the difference in vulnerability.
First, AMPA or kainate exposures appeared to trigger substantial
mitochondrial Ca2+ loading in motor neurons, as
indicated by a sharp increase in intracellular Ca2+
after addition of the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenyl hydrazone (FCCP) after the
agonist exposure. The same exposures caused little mitochondrial
Ca2+ accumulation in GABAergic cortical neurons.
Subsequent experiments examined other measures of mitochondrial
function to compare sequelae of AMPA/kainate receptor activation
between these populations. Brief exposure to either AMPA or kainate
caused mitochondrial depolarization, assessed using
tetramethylrhodamine ethylester, and reactive oxygen species (ROS)
generation, assessed using hydroethidine, in motor neurons. However,
these effects were only seen in the GABAergic neurons after exposure to
the nondesensitizing AMPA receptor agonist kainate. Finally, addition
of either antioxidants or toxins (FCCP or CN ) that
block mitochondrial Ca2+ uptake attenuated
AMPA/kainate receptor-mediated motor neuron injury, suggesting that the
mitochondrial Ca2+ uptake and consequent ROS
generation are central to the injury process.
Key words:
glutamate; kainate; hydroethidine; oxidative stress; mitochondria; GABA; ALS
Copyright © 2000 Society for Neuroscience 0270-6474/0/201240-11$05.00/0
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