A Missense Mutation of the Gene Encoding Synaptic Vesicle Glycoprotein 2A (SV2A) Confers Seizure Susceptibility by Disrupting Amygdalar Synaptic GABA Release

Tokudome, Kentaro; Okumura, Takahiro; Terada, Ryo; Shimizu, Saki; Kunisawa, Naofumi; Mashimo, Tomoji; Serikawa, Tadao; Sasa, Masashi; Ohno, Yukihiro

doi:10.3389/fphar.2016.00210

Cited by 23 publications

(23 citation statements)

References 44 publications

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“…On the other hand, rats with a mutated form of SV2A are more susceptible to PTZ treatment and present a reduction of depolarization-induced GABA release in the hippocampus and the amygdala but no changes in depolarization-induced glutamate release (Tokudome et al, 2016a,b), linking again specifically SV2A with the GABAergic network. This is truly surprising as the presence of SV2A in glutamatergic synapses has been proven by a broad range of techniques.…”

Section: Discussionmentioning

confidence: 99%

Puzzling Out Synaptic Vesicle 2 Family Members Functions

Bartholomé

Ackerveken

Gil

et al. 2017

Front. Mol. Neurosci.

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Synaptic vesicle proteins 2 (SV2) were discovered in the early 80s, but the clear demonstration that SV2A is the target of efficacious anti-epileptic drugs from the racetam family stimulated efforts to improve understanding of its role in the brain. Many functions have been suggested for SV2 proteins including ions or neurotransmitters transport or priming of SVs. Moreover, several recent studies highlighted the link between SV2 and different neuronal disorders such as epilepsy, Schizophrenia (SCZ), Alzheimer’s or Parkinson’s disease. In this review article, we will summarize our present knowledge on SV2A function(s) and its potential role(s) in the pathophysiology of various brain disorders.

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Section: Discussionmentioning

confidence: 99%

Puzzling Out Synaptic Vesicle 2 Family Members Functions

Bartholomé

Ackerveken

Gil

et al. 2017

Front. Mol. Neurosci.

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“…However, hippocampal slice recordings from SV2A knockout animals showed a more pronounced effect on inhibitory postsynaptic currents . Furthermore, SV2A missense mutation showed a preferential disruption of action potential‐induced GABA, but not glutamate, release . Similarly, treatment of epileptic animals (lithium‐pilocarpine model) with clinically relevant doses of LEV also had a differential effect on neurotransmitter levels measured by microdialysis in the hippocampus .…”

Section: Levetiracetammentioning

confidence: 98%

“…35 Furthermore, SV2A missense mutation showed a preferential disruption of action potential-induced GABA, but not glutamate, release. 31,32,36 Similarly, treatment of epileptic animals (lithium-pilocarpine model) with clinically relevant doses of LEV also had a differential effect on neurotransmitter levels measured by microdialysis in the hippocampus. 37 LEV-treated epileptic rats had higher GABA levels in response to potassium-induced depolarization than vehicle-treated epileptic rats.…”

Section: Key Pointsmentioning

confidence: 99%

“…Heterozygous SV2A mice, lacking approximately 50% of the protein, require much lower number of stimulations to reach fully kindled state in both corneal and amygdala kindling models . SV2A‐targeted missense mutation also facilitates PTZ kindling in rats …”

Section: Levetiracetammentioning

confidence: 99%

“…30 SV2A-targeted missense mutation also facilitates PTZ kindling in rats. 31,32 Furthermore, SV2A expression is reduced in a rat post-SE model of epilepsy during both the latent period and chronic phase with spontaneous recurrent seizures (SRS) 33 and is also reduced in the spontaneously epileptic rat. 29,34 SV2A knockout animals develop severe epilepsy early in their ontogeny.…”

Section: Key Pointsmentioning

confidence: 99%

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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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