The Journal of Neuroscience, May 15, 2002, 22(10):3969-3976
Signaling Cascade Regulating Long-Term Potentiation of
GABAA Receptor Responsiveness in Cerebellar Purkinje
Neurons
Shin-ya
Kawaguchi and
Tomoo
Hirano
Department of Biophysics, Graduate School of Science, Kyoto
University, Sakyo-ku, Kyoto 606-8502, Japan, and Core Research for
Evolutional Science and Technology, Japan Science and Technology
Corporation, Kawaguchi, Saitama 332-0012, Japan
Synaptic plasticity, a cellular basis of learning and memory, has
been studied extensively at excitatory synapses. Although synaptic
plasticity has also been reported at inhibitory synapses, the molecular
mechanism remains elusive. Here we attempted to clarify the overall
signaling cascades regulating the induction of inhibitory synaptic
plasticity in the cerebellum.
Rebound potentiation (RP), a long-lasting increase in GABAA
receptor (GABAAR) responsiveness, is induced by
postsynaptic depolarization of a Purkinje neuron (PN) at synapses
formed with inhibitory interneurons (stellate or basket neurons).
Previously, we showed that RP is suppressed by homosynaptic
activation during depolarization through activation of the
postsynaptic GABAB receptor (GABABR).
Activation of GABABR reduces cAMP-dependent protein kinase
(PKA) activity via the Gi/Go-protein.
Here we examined the molecular pathway through which PKA activity
affects RP induction.
We confirmed that inhibition of
Ca2+/calmodulin-dependent protein kinase II (CaMKII)
or PKA suppresses RP. We also found that inhibition of
protein phosphatase 1 (PP-1) or calcineurin (PP-2B) impaired
suppression of RP induction. Inhibition of either PP-1 or calcineurin
abolished RP impairment by PKA inhibition, but not that by CaMKII
inhibition. Antisense oligonucleotide-mediated knock down of DARPP-32,
which is a substrate of PKA and calcineurin and inhibits PP-1 when
phosphorylated by PKA, suppressed RP. Furthermore, activation of
GABABR inhibited CaMKII activation through PKA inhibition and PP-1 activity. These results suggest that calcineurin activation accompanied by PKA inhibition in a PN causes dephosphorylation of
DARPP-32, which releases PP-1 from inhibition. PP-1 in turn inhibits
CaMKII activity, which is then directly involved in the RP induction.
Key words:
synaptic plasticity; inhibitory synapse; GABA; Purkinje
neuron; PP-1; calcineurin; DARPP-32; CaMKII; PKA
Copyright © 2002 Society for Neuroscience 0270-6474/02/22103969-08$05.00/0
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