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Brivaracetam augments short‐term depression and slows vesicle recycling
Author(s) -
Yang Xiaofeng,
Bognar Joseph,
He Tianyu,
Mohammed Mouhari,
Niespodziany Isabelle,
Wolff Christian,
Esguerra Manuel,
Rothman Steven M.,
Dubinsky Janet M.
Publication year - 2015
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13223
Subject(s) - excitatory postsynaptic potential , synaptic vesicle , stimulation , postsynaptic potential , chemistry , neuroscience , hippocampal formation , medicine , endocrinology , anesthesia , biology , vesicle , inhibitory postsynaptic potential , biochemistry , receptor , membrane
Summary Objective Brivaracetam ( BRV ) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A ( SV 2A) with a higher affinity than the antiepileptic drug levetiracetam ( LEV ). Experiments were performed to determine if BRV acted similarly to LEV to induce or augment short‐term depression ( STD ) under high‐frequency neuronal stimulation and slow synaptic vesicle recycling. Methods Electrophysiologic field excitatory postsynaptic potential (f EPSP ) recordings were made from CA 1 synapses in rat hippocampal slices loaded with BRV or LEV during intrinsic activity or with BRV actively loaded during hypertonic stimulation. STD was examined in response to 5 or 40 Hz stimulus trains. Presynaptic release of FM 1‐43 was visualized using two‐photon microscopy to assess drug effects upon synaptic vesicle mobilization. Results When hippocampal slices were incubated in 0.1–30 μ m BRV or 30 μ m –1 m m LEV for 3 h, the relative CA 1 field EPSP s decreased over the course of a high‐frequency train of stimuli more than for control slices. This STD was frequency‐ and concentration‐dependent, with BRV being 100‐fold more potent than LEV . The extent of STD depended on the length of the incubation time for both drugs. Pretreatment with LEV occluded the effects of BRV . Repeated hypertonic sucrose treatments and train stimulation successfully unloaded BRV from recycling vesicles and reversed BRV s effects on STD , as previously reported for LEV . At their maximal concentrations, BRV slowed FM 1‐43 release to a greater extent than in slices loaded with LEV during prolonged stimulation. Significance BRV , similar to LEV , entered into recycling synaptic vesicles and produced a frequency‐dependent decrement of synaptic transmission at 100‐fold lower concentrations than LEV . In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV , suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV 2A to curb synaptic transmission and limit epileptic activity.