Abstract
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.
Highlights
Levetiracetam ((S)-a-ethyl-2-oxo-pyrrolidine acetamide) represents a new class of drug for the treatment of neurological and psychiatric disorders
SV2AEGFP trafficked to presynaptic terminals in wild-type neurons, where it co-localized with the synaptic vesicle protein synaptotagmin and synaptophysin (Figure 1)
The results presented here demonstrate that overexpression of Synaptic Vesicle Protein 2A (SV2A) produces abnormal neurotransmission that can be rescued by treatment with levetiracetam
Summary
Levetiracetam ((S)-a-ethyl-2-oxo-pyrrolidine acetamide) represents a new class of drug for the treatment of neurological and psychiatric disorders. The protein receptor for levetiracetam is Synaptic Vesicle Protein 2A (SV2A) [13], a membrane glycoprotein specific to the secretory vesicles of neurons and endocrine cells in vertebrates [14]. SV2A is both necessary and sufficient for levetiracetam binding [13]. Mice heterozygous for the SV2A gene disruption show reduced response to drug treatment [15], consistent with SV2A being required for levetiracetam action. Levetiracetam appears to act by modulating the action of SV2A, though its mechanism of action remains unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
