TY - JOUR T1 - Levetiracetam inhibits SV2A-synaptotagmin interaction at synapses that lack SV2B JF - bioRxiv DO - 10.1101/640185 SP - 640185 AU - Kristine Ciruelas AU - Daniele Marcotulli AU - Jane M Sullivan AU - Sandra M Bajjalieh Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/05/21/640185.abstract N2 - Epilepsy remains a difficult-to-treat neurological disorder prompting the need for new therapies that work via alternate mechanisms. Levetiracetam (LEV) is the first in a series of anti-epilepsy drugs that target presynaptic functioning. LEV binds the synaptic vesicle protein SV2A, and has been shown to decrease neurotransmitter release in hippocampal slices. The molecular basis of LEV action is unknown, however, and direct effects of LEV on SV2A function remain to be determined. SV2A is the most widely expressed paralog of a three-gene family (SV2A, B, C) that is variably co-expressed throughout the CNS. All three SV2s bind the calcium sensor protein synaptotagmin and SV2 plays a crucial role in synaptotagmin stability and trafficking. Here we addressed the action of LEV at the cellular and molecular level asking whether the presence of non-LEV binding SV2 paralogs influences drug action and whether LEV impacts SV2A’s role in synaptotagmin function. We report that LEV altered short-term synaptic plasticity in isolated neurons from SV2B knockout but not wild-type mice, mimicking the loss of SV2 function. Similarly, LEV reduced SV2A binding to synaptotagmin only in the absence of SV2B. Furthermore, LEV reduced and slowed the internalization of synaptotagmin in neurons cultured from SV2B KO but not WT mice. Taken together, these findings suggest that LEV alters synaptic release probability by disrupting SV2’s regulation of synaptotagmin selectively in neurons that express only SV2A. Neurons that meet this requirement include most inhibitory neurons and the granule cells of the dentate gyrus, two classes of neuron implicated in epilepsy. ER -