Abstract
Epilepsy is a serious neurological disease characterized by recurrent unprovoked seizures. The exact etiology of epilepsy is not fully understood. Protrudin is a neural membrane protein and is found to be mutated in hereditary spastic paraplegia that characterized by symptoms like seizures. Here, we reported that the expression of protrudin was downregulated in the temporal neocortex of epileptic patients and in the hippocampus and cortex of pentylenetetrazol and kainic acid-kindled epileptic mouse models. Behavioral and electroencephalogram analyses indicated that overexpression of protrudin in the mouse hippocampus increased the latency of the seizure and decreased the frequency and duration of seizure activity. Using whole-cell patch clamp, overexpression of protrudin in the mouse hippocampus resulted in a reduction in action potential frequency and an increase in gamma-aminobutyric acid (GABA)ergic inhibitory current amplitude. Moreover, western blot analysis showed that the membrane expression of the GABA A receptor β2/3 subunit was also upregulated after protrudin overexpression, and coimmunoprecipitation resulted in a protein–protein interaction between protrudin, GABAARβ2/3 and GABA receptor-associated protein in the hippocampus of epileptic mice. These findings suggest that protrudin probably inhibits the occurrence and development of epilepsy through the regulation of GABAA receptor-mediated synaptic transmission, and protrudin might be a promising target for the treatment of epilepsy.
Highlights
Epilepsy is a devastating neurological disease and is characterized by recurrent seizure activity
We further explored whether the interaction of protrudin with GABAARβ2/3 or GABA receptor-associated protein (GABARAP) is altered in a PTZ-kindled epileptic mouse model after protrudin overexpression
In the present study, we reported that protrudin modulates seizure activity by regulating the GABAARsmediated inhibitory synaptic currents and the surface expression of GABAARs
Summary
Epilepsy is a devastating neurological disease and is characterized by recurrent seizure activity. Epilepsy has a worldwide prevalence of ~ 1–2% with ~ 65 million people suffering in the world[1]. Almost 30% of newly diagnosed epileptic patients fail to respond to antiepileptic drugs and develop pharmacoresistant and intractable epilepsy[2]. As the most common form of intractable epilepsy, temporal lobe epilepsy (TLE) often results in poor prognoses[3]. Epileptic seizures are generally accepted to be attributed to an imbalance of excitatory and inhibitory synaptic transmission[2]. The exact etiology and pathogenesis of epilepsy still have an incomplete
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