Expression pattern of synaptic vesicle protein 2 (<scp>SV</scp>2) isoforms in patients with temporal lobe epilepsy and hippocampal sclerosis

Crevecoeur, Julie; Kaminski, RM; Rogister, Bernard; Foerch, Patrik; Vandenplas, Catherine; Neveux, Michel; Mazzuferi, Manuela; Kroonen, Jérôme; Poulet, Christophe; Martin, Didier; Sadzot, Bernard; Rikir, Estelle; Klitgaard, Henrik; Moonen, Gustave; Deprez, Manuel

doi:10.1111/nan.12054

Cited by 61 publications

(73 citation statements)

References 43 publications

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“…In general, changes in synaptic proteins might parallel synaptic loss or formation (Crevecoeur et al, 2013). For example, in sclerotic hippocampus of TLE patients VGLUT-1 expression has been found to be down-regulated in regions with severe neuronal loss, but strongly up-regulated in regions characterized by formation of new glutamaregic synapses (i.e.…”

Section: The Glutamate/gaba Hypothesis: Enhancement Of Excitation mentioning

confidence: 99%

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

et al. 2014

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Epilepsy is a heterogeneous family of neurological disorders that manifest as seizures, i.e. the hypersynchronous activity of large population of neurons. About 30% of epileptic patients do not respond to currently available antiepileptic drugs. Decades of intense research have elucidated the involvement of a number of possible signaling pathways, however, at present we do not have a fundamental understanding of epileptogenesis. In this paper, we review the literature on epilepsy under a wide-angle perspective, a mandatory choice that responds to the recurrent and unanswered question about what is epiphenomenal and what is causal to the disease. While focusing on the involvement of K+ and glutamate/GABA in determining neuronal hyperexcitability, emphasis is given to astrocytic contribution to epileptogenesis, and especially to loss-of-function of astrocytic glutamine synthetase following reactive astrogliosis, a hallmark of epileptic syndromes. We finally introduce the potential involvement of abnormal glycogen synthesis induced by excess glutamate in increasing susceptibility to seizures.

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Section: The Glutamate/gaba Hypothesis: Enhancement Of Excitation mentioning

confidence: 99%

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

et al. 2014

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“…SV2A is homogeneously distributed in the rodent brain (7), whereas other isoforms have discrete distributions suggesting specific functional roles (8). Reduced expression of SV2A and SV2B in areas of synaptic loss in temporal lobe epilepsy and a selective increase in SV2C expression in sprouting mossy fibers in mesial temporal sclerosis have been reported (4), further indicating a role for SV2 in epilepsy and related neurodegeneration. 19 F-UCB-H is a novel ligand with a nanomolar affinity for SV2A and an in silico, in vitro, and in vivo ADME (absorption, distribution, metabolism, and excretion) profile that makes it suitable for consideration as a candidate SV2A PET ligand (10).…”

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confidence: 98%

“…Although the role of some SV proteins has been studied in great detail and their function is generally understood (1,2), other SV proteins require further study. The potential value of SV protein 2 (SV2) isoforms (3)(4)(5) as drug targets has renewed interest in these proteins. The antiepileptic drug levetiracetam (LEV) binds to SV2A (6), suggesting a role for SV2A in the pathology underlying certain forms of epilepsy.…”

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confidence: 99%

Evaluation of ¹⁸F-UCB-H as a Novel PET Tracer for Synaptic Vesicle Protein 2A in the Brain

et al. 2014

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Synaptic vesicle protein 2 isoforms are critical for proper nervous system function and are involved in vesicle trafficking. The synaptic vesicle protein 2A (SV2A) isoform has been identified as the binding site of the antiepileptic levetiracetam (LEV), making it an interesting therapeutic target for epilepsy. 18 F-UCB-H is a novel PET imaging agent with a nanomolar affinity for human SV2A. Methods: Preclinical PET studies were performed with isoflurane-anesthetized rats. The arterial input function was measured with an arteriovenous shunt and a β-microprobe system. 18 F-UCB-H was injected intravenously (bolus of 140 ± 20 MBq). Results: Brain uptake of 18 F-UCB-H was high, matching the expected homogeneous distribution of SV2A. The distribution volume (V t ) for 18 F-UCB-H was calculated with Logan graphic analysis, and the effect of LEV pretreatment on V t was measured. In control animals the whole-brain V t was 9.76 ± 0.52 mL/cm 3 (mean ± SD; n 5 4; test-retest), and the reproducibility in test-retest studies was 10.4% ± 6.5% (mean ± SD). The uptake of 18 F-UCB-H was dose dependently blocked by pretreatment with LEV (0.1-100 mg/kg intravenously). Conclusion: Our results indicated that 18 F-UCB-H is a suitable radiotracer for the imaging of SV2A in vivo. To our knowledge, this is the first PET tracer for the in vivo quantification of SV2A. The necessary steps for the implementation of 18 F-UCB-H production under good manufacturing practice conditions and the first human studies are being planned.

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“…Synaptic vesicle protein 2 (SV2) is a neuronal vesicle membrane glycoprotein that appears to be an important target in treatment of partial and generalized epilepsies [6]. It is thought to decrease neuronal excitability [7] since knockout of synaptic vesicle protein 2A (SV2A) in mice leads to seizures [7].…”

Section: Introductionmentioning

confidence: 99%

“…Gene expression of SV2A is reduced during epileptogenesis in the rat, and changes in expression of SV2A may have consequences for progression of epilepsy [8]. Recent studies have found downregulation of SV2A expression in brain tissue obtained from patients with intractable temporal lobe epilepsy [6,9]. Several lines of evidence suggest that SV2A is the binding site for the antiepileptic drug levetiracetam (LEV) [10,11].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Synaptic Vesicle Protein 2A Inhibits Seizures and Amygdaloid Electroencephalogram Activity in Pilocarpine-induced Pharmacoresistant Epileptic Rats

Wang¹,

Zhou²,

Shi³

et al. 2018

Neuropsychiatry

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Purpose: The present study investigated the role of upregulation of synaptic vesicle protein 2A (SV2A) in seizure control and electroencephalogram (EEG) activity in pilocarpine-induced pharmacoresistant epileptic rats. Methods:A total of 100 healthy adult male Sprague-Dawley rats were used to establish the pilocarpine-induced model of epilepsy. The successful epilepsy model was then used to select for pharmacoresistance by testing seizure responses to phenobarbital and carbamazepine. The selected pharmacoresistant rats were assigned to a pharmacoresistant epileptic group (PRE group, 10 rats) or a SV2A upregulation group (PRU group, 8 rats). Ten pharmacosensitive epileptic rats (PSE group, 10 rats) selected randomly and 10 normal rats (NCR group, 10 rats) served as controls. Immunohistochemistry and western blots were performed to assess SV2A expression in hippocampal tissue samples from all 4 groups. EEG changes and epileptic seizures were recorded by video-EEG and compared among the groups. Results:Immunohistochemical staining showed that SV2A levels increased slightly in the PSE group (0.26 ± 0.018) compared with the NCR group (0.24 ± 0.031). However, SV2A decreased remarkably in the PRE group (0.11 ± 0.121). Western blot analysis yielded similar findings. SV2A increased in the PSE group (4.10 ± 1.127) compared with the NCR group (3.26 ± 0.699) and decreased in the PRE group (1.86 ± 0.421). Frequency and duration of seizures increased in the PRE group as compared with the PSE group. After overexpression of SV2A, levels of SV2A protein increased in the PRU group. In addition, seizure severity, frequency, and duration were decreased compared with the PRE group.

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Expression pattern of synaptic vesicle protein 2 (SV2) isoforms in patients with temporal lobe epilepsy and hippocampal sclerosis

Cited by 61 publications

References 43 publications

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

Evaluation of ¹⁸F-UCB-H as a Novel PET Tracer for Synaptic Vesicle Protein 2A in the Brain

Overexpression of Synaptic Vesicle Protein 2A Inhibits Seizures and Amygdaloid Electroencephalogram Activity in Pilocarpine-induced Pharmacoresistant Epileptic Rats

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Expression pattern of synaptic vesicle protein 2 (SV2) isoforms in patients with temporal lobe epilepsy and hippocampal sclerosis

Cited by 61 publications

References 43 publications

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

Evaluation of 18F-UCB-H as a Novel PET Tracer for Synaptic Vesicle Protein 2A in the Brain

Overexpression of Synaptic Vesicle Protein 2A Inhibits Seizures and Amygdaloid Electroencephalogram Activity in Pilocarpine-induced Pharmacoresistant Epileptic Rats

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Evaluation of ¹⁸F-UCB-H as a Novel PET Tracer for Synaptic Vesicle Protein 2A in the Brain