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Abstract
Although many studies have explored the mechanism of epilepsy, it remains unclear and deserves further investigation. Vezatin has been reported to be a synaptic regulatory protein involved in regulating neuronal synaptic transmission (NST). However, the role of vezatin in epilepsy remains unknown. Therefore, the aims of this study are to investigate the underlying roles of vezatin in epilepsy. In this study, vezatin expression was increased in hippocampal tissues from pilocarpine (PILO)-induced epileptic mice and a Mg2+-free medium-induced in vitro seizure-like model. Vezatin knockdown suppressed seizure activity in PILO-induced epileptic mice. Mechanistically, vezatin knockdown suppressed AMPAR-mediated synaptic events in epileptic mice and downregulated the surface expression of the AMPAR GluA1 subunit (GluA1). Interestingly, vezatin knockdown decreased the phosphorylation of GluA1 at serine 845 and reduced protein kinase A (PKA) phosphorylation; when PKA phosphorylation was suppressed by H-89 (a selective inhibitor of PKA phosphorylation) in vitro, the effects of vezatin knockdown on reducing the phosphorylation of GluA1 at serine 845 and the surface expression of GluA1 were blocked. Finally, we investigated the pattern of vezatin in brain tissues from patients with temporal lobe epilepsy (TLE), and we found that vezatin expression was also increased in patients with TLE. In summary, the vezatin expression pattern is abnormal in individuals with epilepsy, and vezatin regulates seizure activity by affecting AMPAR-mediated NST and the surface expression of GluA1, which is involved in PKA-mediated phosphorylation of GluA1 at serine 845, indicating that vezatin-mediated regulation of epileptic seizures represents a novel target for epilepsy.
Highlights
Epilepsy is a heterogeneous disease with a complicated etiology and mechanism [1, 2]
Immunofluorescence staining showed that vezatin expressed in the hippocampal CA1 region in mice colocalized with the neuronal marker microtubuleassociated protein 2 (MAP2) (Fig. 1c); the mean fluorescence intensity (MFI) of vezatin was higher in the epilepsy group than in the control group, indicating increased expression of vezatin in the epilepsy model (Fig. 1d)
Subsequent electrophysiological studies revealed that vezatin knockdown suppressed CP-AMPARmediated synaptic events and inhibited the surface expression of GluA1 in epileptic mice, indicating that vezatin may regulate amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic events by affecting the surface expression of GluA1
Summary
Epilepsy is a heterogeneous disease with a complicated etiology and mechanism [1, 2]. Many studies have explored the underlying mechanism of epilepsy, the etiology and mechanism of epilepsy remain unclear and require further investigation to potentially aid in the development of new disease-modifying therapies to suppress seizures in patients with epilepsy. Vezatin was found to be expressed at high levels in neuronal dendritic spines and regulates synaptic plasticity in vivo and in vitro [3, 4]. Altered expression of vezatin affects glutamate receptor-mediated neuronal synaptic transmission (NST) [3]. NST dysfunction plays a vital role in the pathophysiological mechanism of epilepsy [2, 7]. Based on the abovementioned functions of vezatin, we hypothesized that vezatin may play a specific role in epilepsy by influencing NST
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