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Published online 18 October 2004. doi:10.1083/jcb.200405032
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 2, 293-302
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Article

Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor



Fubito Nakatsu1,2, Motohiro Okada3, Fumiaki Mori4, Noriko Kumazawa5, Hiroto Iwasa3, Gang Zhu3, Yasufumi Kasagi6, Haruyuki Kamiya8, Akihiro Harada9, Kazuhiro Nishimura10, Arata Takeuchi1,7, Taisuke Miyazaki11, Masahiko Watanabe11, Shigeki Yuasa12, Toshiya Manabe5, Koichi Wakabayashi4, Sunao Kaneko3, Takashi Saito1,7, and Hiroshi Ohno1,2

1 RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan
2 Division of Molecular Membrane Biology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
3 Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki 036-8216, Japan
4 Department of Neuropathology, Institute of Brain Science, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan
5 Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
6 Department of Integrative Neurophysiology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
7 Department of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
8 Division of Cell Biology and Neurophysiology, Department of Neuroscience, Faculty of Medicine, Kobe University, Kobe 650-0017, Japan
9 Laboratory of Cellular and Molecular Morphology, Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan
10 Department of Clinical Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
11 Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
12 Department of Ultrastructural Research, National Institute of Neuroscience, Tokyo 187-8502, Japan

Correspondence to Hiroshi Ohno: ohno{at}rcai.riken.jp

AP-3 is a member of the adaptor protein (AP) complex family that regulates the vesicular transport of cargo proteins in the secretory and endocytic pathways. There are two isoforms of AP-3: the ubiquitously expressed AP-3A and the neuron-specific AP-3B. Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved. To address this question, we generated mice lacking µ3B, a subunit of AP-3B. µ3B–/– mice suffered from spontaneous epileptic seizures. Morphological abnormalities were observed at synapses in these mice. Biochemical studies demonstrated the impairment of {gamma}-aminobutyric acid (GABA) release because of, at least in part, the reduction of vesicular GABA transporter in µ3B–/– mice. This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway. Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles. This work adds a new aspect to the pathogenesis of epilepsy.

F. Nakatsu, M. Okada, and F. Mori contributed equally to this work.

Abbreviations used in this paper: AP, adaptor protein; EC, entorhinal cortex; ES, embryonic stem; GABA, {gamma}-aminobutyric acid; HPS, Hermansky-Pudlak syndrome; LTP, long-term potentiation; Neo, neomycin; PTX, picrotoxin; PTZ, pentylenetetrazole; TA, temporoammonic; VGAT, vesicular GABA transporter.


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