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The Journal of Neuroscience, May 3, 2006, 26(18):4820-4825; doi:10.1523/JNEUROSCI.0535-06.2006

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Brief Communications
Involvement of Basal Protein Kinase C and Extracellular Signal-Regulated Kinase 1/2 Activities in Constitutive Internalization of AMPA Receptors in Cerebellar Purkinje Cells

Tetsuya Tatsukawa,^1,2 Takahiko Chimura,¹ Hiroyoshi Miyakawa,² and Kazuhiko Yamaguchi¹

¹Laboratory for Memory and Learning, Brain Science Institute, RIKEN, Saitama 351-0198, Japan, and ²Laboratory of Cellular Neurobiology, Graduate School of Life Sciences, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan

Correspondence should be addressed to Dr. Kazuhiko Yamaguchi, Laboratory for Memory and Learning, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: yamaguchi{at}brain.riken.jp

AMPA receptor (AMPAR) internalization provides a mechanism for long-term depression (LTD) in both hippocampal pyramidal neurons and cerebellar Purkinje cells (PCs). Cerebellar LTD at the parallel fiber (PF)–PC synapse is the underlying basis of motor learning and requires AMPAR activation, a large Ca²⁺ influx, and protein kinase C (PKC) activation. However, whether these requirements affect the constitutive AMPAR internalization in PF–PC synapses remains unclarified. Tetanus toxin (TeTx) infusion into PCs decreased PF-EPSC amplitude to 60% within 20–30 min (TeTx rundown), without change in paired-pulse facilitation ratio or receptor kinetics. Immunocytochemically measured glutamate receptor 2 (GluR2) internalization ratio decreased at the steady state of TeTx rundown. TeTx rundown did not require AMPAR activity nor an increase in intracellular Ca²⁺ concentration. TeTx rundown was suppressed partially by the inhibition of either conventional PKC or mitogen-activated protein kinase kinase (MEK) and completely by the inhibition of both kinases. The background PKC activity was shown to be sufficient, because a PKC activator did not facilitate TeTx rundown. The inhibition of protein phosphatase 1/2A (PP1/2A) enhanced TeTx rundown slightly, and both inhibition of PP1/2A and activation of PKC maximized it, but one-half of AMPARs at PF–PC synapses remained in the TeTx-resistant pool. The inhibition of actin depolymerization suppressed TeTx rundown and decreased the GluR2 internalization ratio. In contrast, the inhibition of actin polymerization enhanced TeTx rundown and increased the GluR2 internalization ratio. We suggest that the regulation of actin polymerization is involved in the surface expression of AMPARs and the surface expressing AMPARs are constitutively internalized through both basal PKC and MEK–ERK1/2 (extracellular signal-regulated kinase 1/2) activities at PF–PC synapses.

Key words: AMPA receptor; trafficking; PKC; ERK1/2; actin; LTD

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Received Sept. 21, 2005; revised March 31, 2006; accepted April 2, 2006.

Correspondence should be addressed to Dr. Kazuhiko Yamaguchi, Laboratory for Memory and Learning, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: yamaguchi{at}brain.riken.jp

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