Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor.
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 mu3B, a subunit of AP-3B. mu3B-/- 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 mu3B-/- 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.
Nakatsu
Fubito
F
RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan.
Okada
Motohiro
M
Mori
Fumiaki
F
Kumazawa
Noriko
N
Iwasa
Hiroto
H
Zhu
Gang
G
Kasagi
Yasufumi
Y
Kamiya
Haruyuki
H
Harada
Akihiro
A
Nishimura
Kazuhiro
K
Takeuchi
Arata
A
Miyazaki
Taisuke
T
Watanabe
Masahiko
M
Yuasa
Shigeki
S
Manabe
Toshiya
T
Wakabayashi
Koichi
K
Kaneko
Sunao
S
Saito
Takashi
T
Ohno
Hiroshi
H
D033963:Adaptor Protein Complex 3; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002966:Clathrin / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004594:Electrophysiology; D050485:GABA Plasma Membrane Transport Proteins; D005838:Genotype; D005971:Glutamates / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D026901:Membrane Transport Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008954:Models, Biological; D008957:Models, Genetic; D018377:Neurotransmitter Agents; D020033:Protein Isoforms; D011995:Recombination, Genetic; D012640:Seizures; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
D033963:Adaptor Protein Complex 3; D033942:Adaptor Proteins, Vesicular Transport; D002966:Clathrin; D004268:DNA-Binding Proteins; D050485:GABA Plasma Membrane Transport Proteins; D005971:Glutamates; D026901:Membrane Transport Proteins; D018377:Neurotransmitter Agents; D020033:Protein Isoforms; D014157:Transcription Factors