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The Journal of Neurophysiology Vol. 82 No. 3 September 1999, pp. 1569-1576
Copyright ©1999 by the American Physiological Society
1Departments of Neuroscience and Neurology,
Albert Einstein College of Medicine, Bronx, New York 10461;
2Department of Medicinal Chemistry,
Reyes-Harde, Magali,
Barry V. L. Potter,
Antony Galione, and
Patric K. Stanton.
Induction of Hippocampal LTD Requires Nitric-Oxide-Stimulated PKG
Activity and Ca2+ Release From Cyclic ADP-Ribose-Sensitive
Stores. J. Neurophysiol. 82: 1569-1576, 1999. Long-term depression (LTD) of synaptic transmission can
be induced by several mechanisms, one thought to involve
Ca2+-dependent activation of postsynaptic nitric oxide (NO)
synthase and subsequent diffusion of NO to the presynaptic terminal. We used the stable NO donor
S-nitroso-N-acetylpenicillamine (SNAP) to
study the NO-dependent form of LTD at Schaffer collateral-CA1 synapses
in vitro. SNAP (100 µM) enhanced the induction of LTD via a cascade
that was blocked by the N-methyl-D-aspartate
receptor antagonist D-2-amino-5-phosphonopentanoic acid (50 µM), NO guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a]
quinoxalin-1-one (10 µM), and the PKG inhibitor KT5823 (1 µM). We
further show that LTD induced by low-frequency stimulation in the
absence of SNAP also is blocked by KT5823 or
Rp-8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphorothioate
(10 µM), cyclic guanosine 3',5' monophosphate-dependent protein
kinase (PKG) inhibitors with different mechanisms of action.
Furthermore SNAP-facilitated LTD was blocked when release from
intracellular calcium stores was inhibited by ryanodine (10 µM).
Finally, two cell-permeant antagonists of the cyclic ADP-ribose binding
site on ryanodine receptors also were able to block the induction of
LTD. These results support a cascade for induction of homosynaptic,
NO-dependent LTD involving activation of guanylyl cyclase, production
of guanosine 3',5' cyclic monophosphate and subsequent PKG activation.
This process has an additional requirement for release of
Ca2+ from ryanodine-sensitive stores, perhaps dependent on
the second-messenger cyclic ADP ribose.
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