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The Journal of Neuroscience, May 15, 2002, 22(10):3969-3976

Signaling Cascade Regulating Long-Term Potentiation of GABA_A 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 GABA_A receptor (GABA_AR) 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 GABA_B receptor (GABA_BR). Activation of GABA_BR reduces cAMP-dependent protein kinase (PKA) activity via the G_i/G_o-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 GABA_BR 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

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22103969-08$05.00/0

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