CPEB3 can regulate seizure susceptibility by inhibiting the transcriptional activity of STAT3 on NMDARs expression
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Background
The pathogenesis of epilepsy is complex, and current antiepileptic drugs do not effectively control the seizures. Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) regulates neuronal excitability, but its mechanism of action in epilepsy is not clear. In this paper, we investigated the effect of CPEB3 on seizures and elucidated its underlying molecular mechanism.
Methods
Bioinformatics-based search for genes closely associated with epilepsy. Changes in expression and cellular localization of CPEB3 in epilepsy were verified by western blotting (WB) and Immunofluorescence staining. Subsequently, The adeno-associated virus was employed to overexpress or knockdown in mice. Behavioral experiments verified the effect of CPEB3 on epileptic phenotype, and the molecular mechanism of CPEB3 affecting epileptic phenotype was explored by WB, real-time quantitative polymerase chain reaction (RT-qPCR), RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (CHIP).
Results
The results were that CPEB3 was downregulated epilepsy in model mice and patients with temporal lobe epilepsy and co-expressed with neurons. Behavioral experiments have shown that CPEB3 negatively regulates epilepsy phenotype in mice. In addition, exogenous CPEB3 can also bind to the mRNA of signal transducer and activator of transcription 3 (STAT3) and inhibit its translation, resulting in lower levels of STAT3 and p-STAT3, reduced nuclear translocation of STAT3, and decreased STAT3-mediated transcriptional activity of GluN1, GluN2A, and GluN2B, suppressing the expression of NMDAR subunits, which attenuate the seizure degree and susceptibility of epileptic mice.
Conclusion
These findings suggest that CPEB3 may influence excitability and susceptibility in epileptic mice by regulating STAT3 translation and transcriptional activities to promote NMDARs expression. This mechanism could offer insights into novel therapeutic targets for epilepsy.
