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Inhibition of neuronal pentraxin 2 relieved epileptic seizure via reducing GluA1 phosphorylation

Mengnan Xing,Xinlei Yang,Sinan Jin,Xiangping Xu

Neuronal pentraxin 2 (Nptx2), a member of the synaptic protein family linked to excitatory synaptic formation, is found to be upregulated in epileptic mice, yet its role in epilepsy has been unclear. In vivo, we constructed a mouse model of epilepsy by using kainic acid induction. In vitro experiments, a Mg 2+ -free medium was used to induce epileptiform discharges in neurons. The results showed that the Nptx2 was upregulated in epileptic mice. Moreover, Nptx2 knockdown reduced the number of seizures and seizure duration. Knocking down Nptx2 not only reduced the number and duration of seizures but also showed a decrease in electroencephalogram amplitude. Behavioral tests indicated improvements in learning and memory abilities after Nptx2 knockdown. The Nissl staining and Timms staining revealed that Nptx2 silencing mitigated epilepsy-induced brain damage. The immunofluorescence staining revealed that Nptx2 absence resulted in a reduction of apoptosis. Nptx2 knockdown reduced Bax, cleaved caspase3, and cleaved caspase9 expression, while increased Bcl-2 expression. Notably, Nptx2 knockdown inhibited GluA1 phosphorylation at the S831 site and reduced the GluA1 membrane expression. The PSD95 expression declined in the epilepsy model, while the Nptx2 knockdown reversed it. Collectively, our study indicated that Nptx2 silencing not only alleviated brain damage and neuron apoptosis but also improved learning and memory ability in epileptic mice, suggesting Nptx2 as a promising target for epilepsy treatment. Significant statement Nptx2 is associated with excitatory synaptic formation, while the role of Nptx2 in epilepsy remains unclear. Our finding indicated an upregulation of Nptx2 in epileptic mice, and knockdown of Nptx2 leading to a reduction in seizure frequency and duration, alongside improvements in learning and memory. Nptx2 knockdown alleviated neuron apoptosis. More importantly, GluA1 phosphorylation in the S831 site was increased in KA mice, while knockdown of Nptx2 reversed it. Nptx2 knockdown decreased the GluA1 membrane expression. Overall, our study suggested that Nptx2 silencing alleviated brain damage and inhibited neuron apoptosis. This study offers novel insights into epilepsy treatment.