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Journal of Neuroscience, Vol 15, 5098-5105, Copyright © 1995 by Society for Neuroscience
An evaluation of the nitric oxide/cGMP/cGMP-dependent protein kinase cascade in the induction of cerebellar long-term depression in culture
DJ Linden, TM Dawson and VL Dawson
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Cerebellar long-term depression (LTD) is a model system of information
storage in which a persistent attenuation of the parallel fiber- Purkinje
neuron (PN) synapse is induced by conjunctive stimulation of parallel fiber
and climbing fiber inputs at low frequency. As some studies have suggested
that release of the gaseous second messenger, nitric oxide (NO), in the
molecular layer and the consequent activation of soluble guanylate cyclase
and cGMP-dependent protein kinase (PKG) in the PN, is necessary for LTD
induction, we have further examined this hypothesis using a cell culture
protocol. In cerebellar cultures made from transgenic mice in which the
gene for neuronal nitric oxide synthase (nNOS) has been rendered null, LTD
induced by glutamate/depolarization conjunctive stimulation was
indistinguishable from that in cultures from wild-type mice in terms of
amplitude, rate of onset, and duration. Bath application of cGMP analogs
produced a large (80%), transient attenuation of glutamate-gated inward
currents. However, application of an activator of soluble guanylate cyclase
or an inhibitor of type V cGMP-phosphodiesterase did not mimic the effect
of cGMP analogs, and inclusion of cGMP analogs in the patch pipette did not
give rise to a slowly developing attenuation, suggesting that these
compounds exert their effects at the cell surface. Free Ca was measured in
the distal dendritic arbor of single PNs by fura-2
microfluorimetry.(ABSTRACT TRUNCATED AT 250 WORDS)
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