Preferential increase in the hippocampal synaptic vesicle protein 2A (SV2A) by pentylenetetrazole kindling

Ohno, Yukihiro; Ishihara, Shizuka; Terada, Ryo; Kikuta, Miki; Sofue, Nobumasa; Kawai, Yoshiko; Serikawa, Tadao; Sasa, Masashi

doi:10.1016/j.bbrc.2009.09.035

Cited by 40 publications

(37 citation statements)

References 21 publications

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“…Ohno et al. (2009) also has reported a preferential increase in the hippocampal SV2A following pentylenetetrazole kindling. The lack of more robust changes in the present study may be related to strain background since these animals were not on a C57Bl/J background.…”

Section: Discussionmentioning

confidence: 90%

“…As seen previously, there was an ipsilateral increase in 7SC, but there was no significant genotype‐specific difference (note that both ratios are above one in both genotypes suggesting only a kindling effect). Similarly, total levels of SV2 increased and NSF decreased in both kindled Tom +/+ and Tom −/− mice, as previously reported for other kindling models (Matveeva et al., 2007; Ohno et al., 2009). There was no significant genotype‐specific difference as seen by the fact the NSF and SV2 levels for both genotypes are below one and above one, respectively, again suggesting only a kindling effect.…”

Section: Resultsmentioning

confidence: 99%

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Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn‐1 gene

et al. 2017

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IntroductionIn kindling, repeated electrical stimulation of certain brain areas causes progressive and permanent intensification of epileptiform activity resulting in generalized seizures. We focused on the role(s) of glutamate and a negative regulator of glutamate release, STXBP5/tomosyn‐1, in kindling.MethodsStimulating electrodes were implanted in the amygdala and progression to two successive Racine stage 5 seizures was measured in wild‐type and STXBP5/tomosyn‐1−/− (Tom−/−) animals. Glutamate release measurements were performed in distinct brain regions using a glutamate‐selective microelectrode array (MEA).ResultsNaïve Tom−/− mice had significant increases in KCl‐evoked glutamate release compared to naïve wild type as measured by MEA of presynaptic release in the hippocampal dentate gyrus (DG). Kindling progression was considerably accelerated in Tom−/− mice, requiring fewer stimuli to reach a fully kindled state. Following full kindling, MEA measurements of both kindled Tom+/+ and Tom−/− mice showed significant increases in KCl‐evoked and spontaneous glutamate release in the DG, indicating a correlation with the fully kindled state independent of genotype. Resting glutamate levels in all hippocampal subregions were significantly lower in the kindled Tom−/− mice, suggesting possible changes in basal control of glutamate circuitry in the kindled Tom−/− mice.ConclusionsOur studies demonstrate that increased glutamate release in the hippocampal DG correlates with acceleration of the kindling process. Although STXBP5/tomosyn‐1 loss increased evoked glutamate release in naïve animals contributing to their prokindling phenotype, the kindling process can override any attenuating effect of STXBP5/tomosyn‐1. Loss of this “braking” effect of STXBP5/tomosyn‐1 on kindling progression may set in motion an alternative but ultimately equally ineffective compensatory response, detected here as reduced basal glutamate release.

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Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn‐1 gene

et al. 2017

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“…It binds to SV2A protein and suppresses Ca2+ mobilization from the endoplasmic reticulum via binding to neuronal synaptic vesicle protein (SV) 2A (Kaminski et al, 2008). The hippocampal level of SV2A, a primary action site of LEV, was significantly elevated by PTZ kindling (Ohno et al, 2009). Since the anticonvulsive action of LEV is closely associated with the expression level of SV2A in the brain (Kaminski et al, 2008), the fact that may explain the selectivity of LEV observed in PTZ-kindled animals.…”

Section: Discussionmentioning

confidence: 96%

Omega 3 polyunsaturated fatty acids enhance the protective effect of levetiracetam against seizures, cognitive impairment and hippocampal oxidative DNA damage in young kindled rats

Abdel-Wahab

Shaikh

Khateeb

et al. 2015

Pharmacology Biochemistry and Behavior

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“…An increase in hippocampal SV2A expression was also observed in mice kindled by repeated administration of pentylenetetrazole [43, 44]. Twenty-four hours after the last pentylenetetrazole injection, intense SV2A expression was found in the hilus of the dentate gyrus, but not in other regions, including the stratum lucidum of CA3 and the synaptic layer surrounding CA1 and CA3 pyramidal cells [44].…”

Section: The Role Of Sv2a In Modulating Neuronal Excitability In the mentioning

confidence: 99%

“…In addition, pentylenetetrazole kindling selectively elevated SV2A expression in GABAergic interneurons located in the hilus of the DG, but not in mossy glutamatergic fibers [44]. The authors postulate that increased SV2A expression in the hippocampus of kindled rats is a compensatory mechanism that facilitates inhibitory GABAergic neurotransmission [43, 44]. …”

Section: The Role Of Sv2a In Modulating Neuronal Excitability In the mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

Löscher¹,

et al. 2016

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The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models. Several lines of preclinical and clinical evidence, including genetics and protein expression changes, support an important role of SV2A in epilepsy pathophysiology. While the functional consequences of SV2A ligand binding are not fully elucidated, studies suggest that subsequent SV2A conformational changes may contribute to seizure protection. Conversely, the recently discovered negative SV2A modulators, such as UCB0255, counteract the anti-seizure effect of levetiracetam and display procognitive properties in preclinical models. More broadly, dysfunction of SV2A may also be involved in Alzheimer’s disease and other types of cognitive impairment, suggesting potential novel therapies for levetiracetam and its congeners. Furthermore, emerging data indicate that there may be important roles for two other SV2 isoforms (SV2B and SV2C) in the pathogenesis of epilepsy, as well as other neurodegenerative diseases. Utilization of recently developed SV2A positron emission tomography ligands will strengthen and reinforce the pharmacological evidence that SV2A is a druggable target, and will provide a better understanding of its role in epilepsy and other neurological diseases, aiding in further defining the full therapeutic potential of SV2A modulation.

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Preferential increase in the hippocampal synaptic vesicle protein 2A (SV2A) by pentylenetetrazole kindling

Cited by 40 publications

References 21 publications

Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn‐1 gene

Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn‐1 gene

Omega 3 polyunsaturated fatty acids enhance the protective effect of levetiracetam against seizures, cognitive impairment and hippocampal oxidative DNA damage in young kindled rats

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

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