Levetiracetam reverses synaptic deficits produced by overexpression of SV2A.
Levetiracetam is an FDA-approved drug used to treat epilepsy and other disorders of the nervous system. Although it is known that levetiracetam binds the synaptic vesicle protein SV2A, how drug binding affects synaptic functioning remains unknown. Here we report that levetiracetam reverses the effects of excess SV2A in autaptic hippocampal neurons. Expression of an SV2A-EGFP fusion protein produced a ∼1.5-fold increase in synaptic levels of SV2, and resulted in reduced synaptic release probability. The overexpression phenotype parallels that seen in neurons from SV2 knockout mice, which experience severe seizures. Overexpression of SV2A also increased synaptic levels of the calcium-sensor protein synaptotagmin, an SV2-binding protein whose stability and trafficking are regulated by SV2. Treatment with levetiracetam rescued normal neurotransmission and restored normal levels of SV2 and synaptotagmin at the synapse. These results indicate that changes in SV2 expression in either direction impact neurotransmission, and suggest that levetiracetam may modulate SV2 protein interactions.
Department of Pharmacology, University of Washington, Seattle, Washington, United States of America.
Amy
A
Nowack
Erik B
EB
Malarkey
Jia
J
Yao
Adam
A
Bleckert
Jessica
J
Hill
Sandra M
SM
Bajjalieh
D000818:Animals; D049452:Green Fluorescent Proteins / Q000378:metabolism; D000077287:Levetiracetam; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D010641:Phenotype; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*; D050857:Synaptotagmins / Q000378:metabolism
D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D011993:Recombinant Fusion Proteins; C489614:Sv2a protein, mouse; C485184:enhanced green fluorescent protein; D050857:Synaptotagmins; D049452:Green Fluorescent Proteins; D000077287:Levetiracetam; D010889:Piracetam