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The Journal of Neuroscience, December 1, 1999, 19(23):10221-10227
Activation of Presynaptic cAMP-Dependent Protein Kinase Is
Required for Induction of Cerebellar Long-Term Potentiation
David J.
Linden and
Sohyun
Ahn
Department of Neuroscience, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205
Cerebellar long-term potentiation (LTP) is a persistent increase in
the strength of the granule cell-Purkinje neuron synapse that occurs
after brief stimulation of granule cell axons at 2-8 Hz. Previous work
has indicated that cerebellar LTP induction requires presynaptic Ca
influx, stimulation of Ca-sensitive adenylyl cyclase, and activation of
PKA. The evidence implicating PKA has come from bath application of
drugs during LTP induction, an approach that does not distinguish
between PKA activation in the presynaptic or postsynaptic cell.
Although bath application of PKA inhibitor drugs (KT5720,
Rp-8CPT-cAMP-S) blocked LTP induction in granule cell-Purkinje neuron
pairs in culture, selective application to granule cell or Purkinje
neuron somata via patch pipettes did not. We hypothesized that
presynaptic PKA activation is required for LTP induction but that drugs
applied to the granule cell soma cannot diffuse to the terminal within
this timescale. To test this hypothesis, we transfected cerebellar
cultures with an expression vector encoding a peptide inhibitor of PKA
[Rous sarcoma virus (RSV)-protein kinase A inhibitor (PKI)].
Transfection of RSV-PKI into presynaptic granule cells, but not
postsynaptic Purkinje neurons or glial cells, blocked LTP induction
produced by either synaptic stimulation or an exogenous cAMP analog. An
expression vector encoding a control peptide with no PKA inhibitory
activity was ineffective. These results show that induction of
cerebellar LTP requires a presynaptic signaling cascade, including Ca
influx, stimulation of Ca-sensitive adenylyl cyclase, and activation of PKA, and argue against a requirement for postsynaptic Ca signals or
their sequelae.
Key words:
granule cell; Purkinje neuron; glia; particle-mediated
gene transfer; synaptic transmission; motor learning.
Copyright © 1999 Society for Neuroscience 0270-6474/99/192310221-07$05.00/0
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