| RRC ID |
37540
|
| 著者 |
Tokudome K, Okumura T, Shimizu S, Mashimo T, Takizawa A, Serikawa T, Terada R, Ishihara S, Kunisawa N, Sasa M, Ohno Y.
|
| タイトル |
Synaptic vesicle glycoprotein 2A (SV2A) regulates kindling epileptogenesis via GABAergic neurotransmission.
|
| ジャーナル |
Sci Rep
|
| Abstract |
Synaptic vesicle glycoprotein 2A (SV2A) is a prototype synaptic vesicle protein regulating action potential-dependent neurotransmitters release. SV2A also serves as a specific binding site for certain antiepileptics and is implicated in the treatment of epilepsy. Here, to elucidate the role of SV2A in modulating epileptogenesis, we generated a novel rat model (Sv2a(L174Q) rat) carrying a Sv2a-targeted missense mutation (L174Q) and analyzed its susceptibilities to kindling development. Although animals homozygous for the Sv2a(L174Q) mutation exhibited normal appearance and development, they are susceptible to pentylenetetrazole (PTZ) seizures. In addition, development of kindling associated with repeated PTZ treatments or focal stimulation of the amygdala was markedly facilitated by the Sv2a(L174Q) mutation. Neurochemical studies revealed that the Sv2a(L174Q) mutation specifically reduced depolarization-induced GABA, but not glutamate, release in the hippocampus without affecting basal release or the SV2A expression level in GABAergic neurons. In addition, the Sv2a(L174Q) mutation selectively reduced the synaptotagmin1 (Syt1) level among the exocytosis-related proteins examined. The present results demonstrate that dysfunction of SV2A due to the Sv2a(L174Q) mutation impairs the synaptic GABA release by reducing the Syt1 level and facilitates the kindling development, illustrating the crucial role of SV2A-GABA system in modulating kindling epileptogenesis.
|
| 巻・号 |
6
|
| ページ |
27420
|
| 公開日 |
2016-6-6
|
| DOI |
10.1038/srep27420
|
| PII |
srep27420
|
| PMID |
27265781
|
| PMC |
PMC4893657
|
| MeSH |
Amino Acid Sequence
Amygdala / physiology
Animals
Epilepsy / physiopathology*
Hippocampus / metabolism
Humans
Kindling, Neurologic / physiology*
Male
Membrane Glycoproteins / chemistry
Membrane Glycoproteins / physiology*
Nerve Tissue Proteins / chemistry
Nerve Tissue Proteins / physiology*
Rats
Rats, Inbred F344
Sequence Homology, Amino Acid
Synaptic Transmission / physiology*
Synaptic Vesicles / metabolism*
gamma-Aminobutyric Acid / metabolism
gamma-Aminobutyric Acid / physiology*
|
| IF |
3.998
|
| 引用数 |
26
|
|
WOS 分野
|
NEUROSCIENCES
|
| リソース情報 |
| ラット |
F344-Sv2am1Kyo (strainID=1056) |
