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The Journal of Neuroscience, June 20, 2007, 27(25):6788-6799; doi:10.1523/JNEUROSCI.1981-07.2007

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Cellular/Molecular
Sustained Structural Change of GABA_A Receptor-Associated Protein Underlies Long-Term Potentiation at Inhibitory Synapses on a Cerebellar Purkinje Neuron

Shin-ya Kawaguchi^1,2 and Tomoo Hirano^1,2

¹Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan, and ²Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan

Correspondence should be addressed to Tomoo Hirano, Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. Email: thirano{at}neurosci.biophys.kyoto-u.ac.jp

Fast inhibitory synaptic transmission is predominantly mediated by GABA_A receptor (GABA_AR) in the CNS. Although several types of neuronal activity-dependent plasticity at GABAergic synapses have been reported, the detailed mechanism is elusive. Here we show that binding of structurally altered GABA_AR-associated protein (GABARAP) to GABA_AR 2 subunit and to tubulin is critical for long-term potentiation [called rebound potentiation (RP)] at inhibitory synapses on a cerebellar Purkinje neuron (PN). Either inhibition of GABARAP association with GABA_AR2 or deletion of tubulin binding region of GABARAP impaired RP. Inhibition of tubulin polymerization also suppressed RP. Thus, precise regulation of GABA_AR2–GABARAP–microtubule interaction is critical for RP. Furthermore, competitive inhibition of GABARAP binding to GABA_AR2 after the RP establishment attenuated the potentiated response, suggesting that GABARAP is critical not only for the induction but also for the maintenance of RP. Fluorescence resonance energy transfer analysis revealed that GABARAP underwent sustained structural alteration after brief depolarization of a PN depending on the activity of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), which is required for the RP induction. The susceptibility of GABARAP to undergo structural alteration was abolished by an amino acid replacement in GABARAP. Furthermore, RP was impaired by expression of the mutant GABARAP with the replacement. Together, we conclude that GABA_AR association with structurally altered GABARAP downstream of CaMKII activation is essential for RP.

Key words: synaptic plasticity; GABA_AR; GABARAP; FRET; microtubule; Purkinje neuron

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Received Feb. 14, 2007; revised May 16, 2007; accepted May 16, 2007.

Correspondence should be addressed to Tomoo Hirano, Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. Email: thirano{at}neurosci.biophys.kyoto-u.ac.jp

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