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

Nakatsu F, Okada M, Mori F, Kumazawa N, Iwasa H, Zhu G, Kasagi Y, Kamiya H, Harada A, Nishimura K, Takeuchi A, Miyazaki T, Watanabe M, Yuasa S, Manabe T, Wakabayashi K, Kaneko S, Saito T, Ohno H - J. Cell Biol. (2004)

Bottom Line: Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved.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.

View Article: PubMed Central - PubMed

Affiliation: RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan.

ABSTRACT
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.

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Increased seizure susceptibility of μ3B−/−ΔNeo mice. (A) Representative electrocorticogram recorded from μ3B−/−ΔNeo mice (n = 7) during the interictal period. Interictal spikes are underlined. (B) Seizure was induced by intravenous administration of PTZ, a GABAA receptor antagonist, in 4-wk-old (left) and 8-wk-old (right) wild-type (closed circle; 4 wk old, n = 6; 8 wk old, n = 5) and μ3B−/−ΔNeo (closed square; 4 wk old, n = 4; 8 wk old, n = 5) mice. Seizure stages were judged as described previously (see Materials and methods). Results are expressed as means ± SEM (* indicates P < 0.05; ** indicates P < 0.01). (C) Seizure development by amygdala kindling. Kindling experiments were performed as described previously (see Materials and methods), and the development of seizure classes in individual animals is plotted against the number of kindling stimulations. (D) Typical afterdischarge of wild-type (top) or μ3B−/−ΔNeo mice (bottom) induced by the first kindling stimulation.
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fig2: Increased seizure susceptibility of μ3B−/−ΔNeo mice. (A) Representative electrocorticogram recorded from μ3B−/−ΔNeo mice (n = 7) during the interictal period. Interictal spikes are underlined. (B) Seizure was induced by intravenous administration of PTZ, a GABAA receptor antagonist, in 4-wk-old (left) and 8-wk-old (right) wild-type (closed circle; 4 wk old, n = 6; 8 wk old, n = 5) and μ3B−/−ΔNeo (closed square; 4 wk old, n = 4; 8 wk old, n = 5) mice. Seizure stages were judged as described previously (see Materials and methods). Results are expressed as means ± SEM (* indicates P < 0.05; ** indicates P < 0.01). (C) Seizure development by amygdala kindling. Kindling experiments were performed as described previously (see Materials and methods), and the development of seizure classes in individual animals is plotted against the number of kindling stimulations. (D) Typical afterdischarge of wild-type (top) or μ3B−/−ΔNeo mice (bottom) induced by the first kindling stimulation.

Mentions: The frequency of birth of μ3B−/−ΔNeo mice was in accordance with Mendelian expectations. The mice were fertile and survived for at least more than one year. Although the μ3B−/−ΔNeo mice appeared normal, some adult mice exhibited spontaneous epileptic seizures upon presentation of such stimuli as positional change (Video 1, available at http://www.jcb.org/cgi/content/full/jcb.200405032/DC1). More than half of the mice suffered from seizures at the age of 15 wk or over. In addition, the electrocorticogram revealed that all of the μ3B−/−ΔNeo mice tested showed an abnormal epileptic pattern, namely, interictal spikes, which was never observed in wild-type mice (Fig. 2 A). These observations prompted us to test the seizure susceptibility of μ3B−/−ΔNeo mice.


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

Nakatsu F, Okada M, Mori F, Kumazawa N, Iwasa H, Zhu G, Kasagi Y, Kamiya H, Harada A, Nishimura K, Takeuchi A, Miyazaki T, Watanabe M, Yuasa S, Manabe T, Wakabayashi K, Kaneko S, Saito T, Ohno H - J. Cell Biol. (2004)

Increased seizure susceptibility of μ3B−/−ΔNeo mice. (A) Representative electrocorticogram recorded from μ3B−/−ΔNeo mice (n = 7) during the interictal period. Interictal spikes are underlined. (B) Seizure was induced by intravenous administration of PTZ, a GABAA receptor antagonist, in 4-wk-old (left) and 8-wk-old (right) wild-type (closed circle; 4 wk old, n = 6; 8 wk old, n = 5) and μ3B−/−ΔNeo (closed square; 4 wk old, n = 4; 8 wk old, n = 5) mice. Seizure stages were judged as described previously (see Materials and methods). Results are expressed as means ± SEM (* indicates P < 0.05; ** indicates P < 0.01). (C) Seizure development by amygdala kindling. Kindling experiments were performed as described previously (see Materials and methods), and the development of seizure classes in individual animals is plotted against the number of kindling stimulations. (D) Typical afterdischarge of wild-type (top) or μ3B−/−ΔNeo mice (bottom) induced by the first kindling stimulation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172536&req=5

fig2: Increased seizure susceptibility of μ3B−/−ΔNeo mice. (A) Representative electrocorticogram recorded from μ3B−/−ΔNeo mice (n = 7) during the interictal period. Interictal spikes are underlined. (B) Seizure was induced by intravenous administration of PTZ, a GABAA receptor antagonist, in 4-wk-old (left) and 8-wk-old (right) wild-type (closed circle; 4 wk old, n = 6; 8 wk old, n = 5) and μ3B−/−ΔNeo (closed square; 4 wk old, n = 4; 8 wk old, n = 5) mice. Seizure stages were judged as described previously (see Materials and methods). Results are expressed as means ± SEM (* indicates P < 0.05; ** indicates P < 0.01). (C) Seizure development by amygdala kindling. Kindling experiments were performed as described previously (see Materials and methods), and the development of seizure classes in individual animals is plotted against the number of kindling stimulations. (D) Typical afterdischarge of wild-type (top) or μ3B−/−ΔNeo mice (bottom) induced by the first kindling stimulation.
Mentions: The frequency of birth of μ3B−/−ΔNeo mice was in accordance with Mendelian expectations. The mice were fertile and survived for at least more than one year. Although the μ3B−/−ΔNeo mice appeared normal, some adult mice exhibited spontaneous epileptic seizures upon presentation of such stimuli as positional change (Video 1, available at http://www.jcb.org/cgi/content/full/jcb.200405032/DC1). More than half of the mice suffered from seizures at the age of 15 wk or over. In addition, the electrocorticogram revealed that all of the μ3B−/−ΔNeo mice tested showed an abnormal epileptic pattern, namely, interictal spikes, which was never observed in wild-type mice (Fig. 2 A). These observations prompted us to test the seizure susceptibility of μ3B−/−ΔNeo mice.

Bottom Line: Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved.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.

View Article: PubMed Central - PubMed

Affiliation: RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus