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The Journal of Neuroscience, July 15, 2002, 22(14):5840-5847
Presynaptic Mitochondrial Calcium Sequestration Influences
Transmission at Mammalian Central Synapses
Brian
Billups and
Ian D.
Forsythe
Department of Cell Physiology and Pharmacology, University of
Leicester, Leicester LE1 9HN, United Kingdom
Beyond their role in generating ATP, mitochondria have a high
capacity to sequester calcium. The interdependence of these functions
and limited access to presynaptic compartments makes it difficult to
assess the role of sequestration in synaptic transmission. We addressed
this important question using the calyx of Held as a model
glutamatergic synapse by combining patch-clamp with a novel
mitochondrial imaging method. Presynaptic calcium current, mitochondrial calcium concentration
([Ca2+]mito, measured using
rhod-2 or rhod-FF), cytoplasmic calcium concentration
([Ca2+]cyto, measured using
fura-FF), and the postsynaptic current were monitored during synaptic
transmission. Presynaptic [Ca2+]cyto
rose to 8.5 ± 1.1 µM and decayed rapidly with a
time constant of 45 ± 3 msec; presynaptic
[Ca2+]mito also rose rapidly to >5
µM but decayed slowly with a half-time of 1.5 ± 0.4 sec. Mitochondrial depolarization with rotenone and carbonyl cyanide
p-trifluoromethoxyphenylhydrazone abolished
mitochondrial calcium rises and slowed the removal of
[Ca2+]cyto by 239 ± 22%. Using
simultaneous presynaptic and postsynaptic patch clamp, combined with
presynaptic mitochondrial and cytoplasmic imaging, we investigated the
influence of mitochondrial calcium sequestration on transmitter
release. Depletion of ATP to maintain mitochondrial membrane
potential was blocked with oligomycin, and ATP was provided in the
patch pipette. Mitochondrial depolarization raised
[Ca2+]cyto and reduced transmitter
release after short EPSC trains (100 msec, 200 Hz); this effect was
reversed by raising mobile calcium buffering with EGTA. Our results
suggest a new role for presynaptic mitochondria in maintaining
transmission by accelerating recovery from synaptic depression after
periods of moderate activity. Without detectable thapsigargin-sensitive
presynaptic calcium stores, we conclude that mitochondria are the major
organelle regulating presynaptic calcium at central glutamatergic terminals.
Key words:
mitochondria; calcium imaging; calyx of Held; short-term
plasticity; rhod-2; rhod-FF; fura-FF
Copyright © 2002 Society for Neuroscience 0270-6474/02/22145840-08$05.00/0
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