SV2A Attenuates Interictal anxiety in Pharmacoresistant Epilepsy via the SYT3-GluA2 Axis

Synaptic vesicle glycoprotein 2A (SV2A) is an established target of antiseizure therapy; however, its role in excitatory synaptic function and downstream postsynaptic machinery remains poorly defined. This study examined whether SV2A limits excitotoxic signaling by recruiting synaptotagmin-3 (SYT3), thereby modulating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA2.

A multilevel strategy was used to define the contribution of SV2A to anxiety in a pharmacoresistant epilepsy (PRE) model. The phenobarbital/phenytoin-resistant PRE phenotype was established in rats using the lithium-pilocarpine paradigm. Lentiviral vectors were delivered to the hippocampal CA1 region for bidirectional manipulation of SV2A expression. Protein abundance and molecular interactions were examined using western blotting, immunofluorescence, co-immunoprecipitation, and molecular docking. Synaptic plasticity was assessed using long-term potentiation (LTP) recordings, and anxiety-related behavior was evaluated using the elevated plus maze and open field test.

A special interaction between SV2A and SYT3 was confirmed at the protein level. PRE rats exhibited pronounced anxiety-like behavior, increased seizure frequency, reduced SV2A expression, and aberrantly potentiated LTP in the CA1 region. Hippocampal SV2A overexpression reduced SYT3 levels, suppressed GluA2 internalization, and attenuated both exaggerated LTP and anxiety-like behavior. Conversely, SV2A knockdown increased SYT3 expression, promoted GluA2 endocytosis, and further aggravated aberrant LTP and anxiety-like behavior.

SV2A plays a pivotal role in interictal anxiety associated with PRE. PRE downregulates SV2A and weakens the SV2A-SYT3 interaction, thereby driving aberrant LTP and the emergence of anxiety-like behavior.