title: Seletracetam enhances short term depression in vitro.
abstract: Seletracetam (SEL), an analog of the antiepileptic drug levetiracetam (LEV), decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle protein SV2A with a higher affinity than LEV. Experiments were performed to determine if SEL, like LEV, reduces the later EPSPs in long trains of stimuli in a manner dependent upon access to the interior of synaptic vesicles and SV2A binding. When hippocampal slices were incubated in 3-30μM SEL for 3h, but not 30 min, the relative amplitude of the CA1 field excitatory synaptic potentials decreased over the course of a train of high frequency stimuli more than for control slices. This short term depression was frequency and dose dependent and largely disappeared when the spontaneous activity during the loading period was removed by cutting the Schaffer collaterals. The SEL effect was also observed in slices loaded during prolonged stimulation at 1Hz, but not 10Hz. Hippocampal slices loaded with both SEL and FM1-43 to visualize synaptic boutons released the FM1-43 in response to prolonged stimulation much more slowly than control slices during prolonged stimulation. Like LEV, SEL produced a frequency-dependent decrement of synaptic transmission that was dependent upon the drug entering recycling synaptic vesicles and compatible with SV2A binding. Previous observations of SV2A binding affinity correlated with the current effect of SEL and the previously reported effect of LEV on synaptic transmission validate SV2A as an extremely attractive target for future antiepileptic drug development.
authors: Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA; Electrophysiology Laboratory, Xuanwu Hospital, Capital Medical University, Beijing, China.
authors: Xiaofeng
authors: X
authors: Yang
authors: Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA.
authors: Anna L
authors: AL
authors: Meehan
authors: Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA; Mercy Clinic Child Neurology, St. Louis, MO, USA.
authors: Steven M
authors: SM
authors: Rothman
authors: Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA. Electronic address: dubin001@umn.edu.
authors: Janet M
authors: JM
authors: Dubinsky
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000927:Anticonvulsants; D011760:Pyrrolidinones; C518915:Seletracetam
keywords: Anticonvulsants; Antiepileptic drugs; Epilepsy; Levetiracetam; SV2A; Seletracetam; Synaptic vesicles