Synaptic vesicle glycoprotein 2A (SV2A) regulates kindling epileptogenesis via GABAergic neurotransmission.
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.
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.
Kentaro
K
Tokudome
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.
Takahiro
T
Okumura
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.
Saki
S
Shimizu
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.|Institute of Experimental Animal Sciences, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Tomoji
T
Mashimo
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Akiko
A
Takizawa
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.|Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Tadao
T
Serikawa
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.
Ryo
R
Terada
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.
Shizuka
S
Ishihara
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.
Naofumi
N
Kunisawa
Nagisa Clinic, Osaka 573-1183, Japan.
Masashi
M
Sasa
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.
Yukihiro
Y
Ohno
D000595:Amino Acid Sequence; D000679:Amygdala / Q000502:physiology; D000818:Animals; D004827:Epilepsy / Q000503:physiopathology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007696:Kindling, Neurologic / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D017386:Sequence Homology, Amino Acid; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C489618:Sv2a protein, rat; D005680:gamma-Aminobutyric Acid