[en] Synaptic vesicle glycoprotein 2A (SV2A) is a presynaptic protein targeted by the antiseizure drug levetiracetam. One or more of the three SV2 genes is expressed in all neurons and is essential to normal neurotransmission. Loss of SV2A results in a seizure phenotype in mice and mutations in humans are also linked to congential seizures. How affecting SV2A action impacts the epileptic phenotype remains unclear, especially among the diverse neuronal populations that regulate network excitability. This study explored how brain structure and function are affected by SV2A conditional knock-out (SV2A-cKO) in specific neural cell subtypes. We show that SV2A-cKO in all neurons of the postnatal brain triggers lethal seizures, suggesting that the seizures observed in earlier knockout models were not due to aberrant brain development. Similar lethal seizures are detected in mice in which the loss of SV2A is limited to GABAergic neurons, whereas loss in excitatory neurons produces no noticeable phenotype. No apparent gender difference was ever observed. Further investigation revealed that SV2A-cKO in different GABAergic interneuron populations induces seizure, with variable timescales and severity. Most notably SV2A-cKO in parvalbumin interneurons (PV+) leads to lethal seizures in young animals, while SV2A-cKO in somatostatin (SST) inhibitory neurons results in seizures that were scarcely observed only in adult mice. These results support the crucial role SV2A plays in PV and SST interneurons and suggest that the action of Levetiracetam may be due largely to effects on a subset of GABAergic interneurons.Significance statement The synaptic vesicle glycoprotein 2A is the target of the antiseizure drug levetiracetam, and the SV2A full knockout in mice induce severe seizures. Still, SV2A function in synapses is yet not fully elucidated, including the neuronal subtypes in which SV2A expression is mandatory or dispensable. In this paper, we demonstrated that SV2A knockout in inhibitory neurons provokes seizure (incl. PV+ and SST+) whereas it does not induce any visible phenotype in excitatory neurons. Our study supports the key role of SV2A in interneuron populations, in the context of epilepsy.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Bartholome, Odile; Nervous System Disorders and Therapy, GIGA Institute, University of Liège, 4000 Liège, Belgium
Neirinckx, Virginie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
De La Brassinne, Orianne; Nervous System Disorders and Therapy, GIGA Institute, University of Liège, 4000 Liège, Belgium
Rogister, Bernard ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, et biochimie humaine
Language :
English
Title :
Synaptic Vesicle glycoprotein 2A knockout in parvalbumin and somatostatin interneurons drives seizures in the postnatal mouse brain.
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