Brivaracetam augments short-term depression and slows vesicle recycling

Xiaofeng Yang, Joseph Bognar, Tianyu He, Mouhari Mohammed, Isabelle Niespodziany, Christian Wolff, Manuel Esguerra, Steven M. Rothman, Janet M Dubinsky

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Summary Objective Brivaracetam (BRV) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A (SV2A) 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 (fEPSP) recordings were made from CA1 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 FM1-43 was visualized using two-photon microscopy to assess drug effects upon synaptic vesicle mobilization. Results When hippocampal slices were incubated in 0.1-30 μm BRV or 30 μm-1 mm LEV for 3 h, the relative CA1 field EPSPs 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 BRVs effects on STD, as previously reported for LEV. At their maximal concentrations, BRV slowed FM1-43 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 SV2A to curb synaptic transmission and limit epileptic activity.

Original languageEnglish (US)
Pages (from-to)1899-1909
Number of pages11
JournalEpilepsia
Volume56
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • Anticonvulsants
  • Antiepileptic drugs
  • Brivaracetam
  • Epilepsy
  • Levetiracetam
  • SV2A
  • Short-term depression
  • Synaptic vesicle recycling

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