RGD Reference Report - Synaptic vesicle glycoprotein 2A (SV2A) regulates kindling epileptogenesis via GABAergic neurotransmission. - Rat Genome Database

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Synaptic vesicle glycoprotein 2A (SV2A) regulates kindling epileptogenesis via GABAergic neurotransmission.

Authors: Tokudome, Kentaro  Okumura, Takahiro  Shimizu, Saki  Mashimo, Tomoji  Takizawa, Akiko  Serikawa, Tadao  Terada, Ryo  Ishihara, Shizuka  Kunisawa, Naofumi  Sasa, Masashi  Ohno, Yukihiro 
Citation: Tokudome K, etal., Sci Rep. 2016 Jun 6;6:27420. doi: 10.1038/srep27420.
RGD ID: 12792961
Pubmed: PMID:27265781   (View Abstract at PubMed)
PMCID: PMC4893657   (View Article at PubMed Central)
DOI: DOI:10.1038/srep27420   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Seizures  IMP 12792961; 12792961 RGD 
Experimental Seizures  ISOSv2a (Rattus norvegicus)12792961; 12792961DNA:mutation:cds:p.L174Q(rat)RGD 
Experimental Seizures  IMP 12792961DNA:mutation:cds:p.L174Q(rat)RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
regulation of gamma-aminobutyric acid secretion  IMP 12792961 RGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
dendrite  IDA 12792961 RGD 
neuronal cell body  IDA 12792961 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
increased kindling response  IMP 12792961; 12792961 RGD 
increased kindling response  IMP 12792961DNA:mutation:cds:p.L174QratRGD 
increased susceptibility to pharmacologically induced seizures  IMP 12792961; 12792961 RGD 
increased susceptibility to pharmacologically induced seizures  IMP 12792961DNA:mutation:cds:p.L174QratRGD 
Objects Annotated

Genes (Rattus norvegicus)
Sv2a  (synaptic vesicle glycoprotein 2a)
Sv2am1Kyo  (synaptic vesicle glycoprotein 2a; ENU induced mutant 1, Kyo,)

Genes (Mus musculus)
Sv2a  (synaptic vesicle glycoprotein 2a)

Genes (Homo sapiens)
SV2A  (synaptic vesicle glycoprotein 2A)

Strains
F344-Sv2am1Kyo  (NA)


Additional Information