Inhibition of Cgkii Suppresses Seizure Activity and Hippocampal Excitation by Regulating the Postsynaptic Delivery of Glua1

Abstract

Background/Aims: The imbalance between excitation and inhibition is a defining feature of epilepsy. GluA1 is an AMPA receptor subunit that can strengthen excitatory synaptic transmission when upregulated in the postsynaptic membrane, which has been implicated in the pathogenesis of epilepsy. cGKII, a cGMP-dependent protein kinase, regulates the GluA1 levels at the plasma membrane. Methods: To explore the role of cGKII in epilepsy, we investigated the expression of cGKII in patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model and then performed behavioral, histological, and electrophysiological analyses by applying either a cGKII agonist or inhibitor in the hippocampus of the animal model. Results: cGKII expression was upregulated in the epileptogenic brain tissues of both humans and rats. Pharmacological activation or inhibition of cGKII induced changes in epileptic behaviors in vivo and epileptic discharges in vitro. Further studies indicated that cGKII activation disrupted the balance of excitation and inhibition due to strengthened AMPAR-mediated excitatory synaptic transmission. Moreover, cGKII regulated epileptic seizures by phosphorylating GluA1 at Ser845 to modulate the expression and function of GluA1 in the postsynaptic membrane. Conclusion: These results suggest that cGKII plays a key role in seizure activity and could be a potential therapeutic target for epilepsy.

S-Ketamine Exerts Antidepressant Effects by Regulating Rac1 Gtpase Mediated Synaptic Plasticity in the Hippocampus of Stressed Rats

“…After blocking with 5% skim milk for 2 hours, the membrane was incubated with primary antibody overnight: Rac1 (1:500, sc-514583, Santa Cruz Biotechnology), Tiam1 (1:500, sc-393315, Santa Cruz Biotechnology), α-chimaerin (1:500, sc-365985, Santa Cruz Biotechnology), Bcr (1:500, sc-104, Santa Cruz Biotechnology), GluR-1 (1:500, sc-13152, Santa Cruz Biotechnology), Synapsin 1(1:500, ab254349, Abcam), and PSD-95 (1:500, sc-32290, Santa Cruz Biotechnology). The speci city of these primary antibodies has been veri ed (Mao et al 2017;Liu et al 2018;Elzinga et al 2013;Gu et al 2018;Groh et al 2014;Tsai et al 2012). The membrane was incubated with a mixture of anti-rabbit IgG (Golden Bridge, Zhongshan, China) and horseradish peroxidase (HRP) for 1 hour at room temperature.…”

Pharmacological inhibition of S6K1 rescues synaptic deficits and attenuates seizures and depression in chronic epileptic rats

“…It was previously reported that actin dynamics regulate AMPA receptor trafficking during synaptic plasticity and reverse the decrease in GluA1 levels in the hippocampus, which was shown to be dysregulated in an epilepsy model. 13 , 14 Therefore, we hypothesize that inhibition of S6K1 activity in chronic epileptic rats may modulate local translation and affect synaptic function and morphology, thereby correcting the multiple phenotypes displayed by epileptic rats.…”