GSK3β Activity Alleviates Epileptogenesis and Limits GluA1 Phosphorylation

Urbańska, Małgorzata; Kazmierska-Grebowska, Paulina; Kowalczyk, Tomasz; Caban, Bartosz; Nader, Karolina; Pijet, Barbara; Kalita, Katarzyna; Gozdz, Agata; Devijver, Herman; Lechat, Benoit; Jaworski, Tomasz; Grajkowska, Wiesława; Sadowski, Krzysztof; Jóźwiak, Sergiusz; Kotulska, Katarzyna; Konopacki, Jan; Leuven, Fred Van; Vliet, Erwin A. van; Aronica, Eleonora; Jaworski, Jacek

doi:10.2139/ssrn.3244885

Cited by 4 publications

(6 citation statements)

References 4 publications

(4 reference statements)

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“…40 In contrast, a genetic mouse model with low GSK3α/β activity displayed greater seizure severity during kainate-induced SE 30 and constitutive GSK3β activation in mice reduced susceptibility to kainate-induced seizures. 41 Gys1 mRNA levels were unaffected in the hippocampal formations of chronic CSE mice. If translated, lowered Gsk3b mRNA levels are expected to influence GYS1 only via post-translational modification.…”

Section: Discussionmentioning

confidence: 90%

“…A study using rat pilocarpine and mouse 6 Hz models found pharmacological inhibition of GSK3β lowered seizure susceptibility 40 . In contrast, a genetic mouse model with low GSK3α/β activity displayed greater seizure severity during kainate‐induced SE 30 and constitutive GSK3β activation in mice reduced susceptibility to kainate‐induced seizures 41 …”

Section: Discussionmentioning

confidence: 99%

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Brain glycogen content is increased in the acute and interictal chronic stages of the mouse pilocarpine model of epilepsy

et al. 2022

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Glucose is the main brain fuel in fed conditions, while astrocytic glycogen is used as supplemental fuel when the brain is stimulated. Brain glycogen levels are decreased shortly after induced seizures in rodents, but little is known about how glycogen levels are affected interictally in chronic models of epilepsy. Reduced glutamine synthetase activity has been suggested to lead to increased brain glycogen levels in humans with chronic epilepsy. Here, we used the mouse pilocarpine model of epilepsy to investigate whether brain glycogen levels are altered, both acutely and in the chronic stage of the model. One day after pilocarpine‐induced convulsive status epilepticus (CSE), glycogen levels were higher in the hippocampal formation, cerebral cortex, and cerebellum. Opposite to expected, this was accompanied by elevated glutamine synthetase activity in the hippocampus but not the cortex. Increased interictal glycogen amounts were seen in the hippocampal formation and cerebral cortex in the chronic stage of the model (21 days post‐CSE), suggesting long‐lasting alterations in glycogen metabolism. Glycogen solubility in the cerebral cortex was unaltered in this epilepsy mouse model. Glycogen synthase kinase 3 beta (Gsk3b) mRNA levels were reduced in the hippocampal formations of mice in the chronic stage, which may underlie the elevated brain glycogen content in this model. This is the first report of elevated interictal glycogen levels in a chronic epilepsy model. Increased glycogen amounts in the brain may influence seizure susceptibility in this model, and this warrants further investigation.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Brain glycogen content is increased in the acute and interictal chronic stages of the mouse pilocarpine model of epilepsy

et al. 2022

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“…Variants in BRCA1-associated protein required for ATM activation-1 cause multifocal seizure syndrome [32, 33]. GSK3B activity protects neuronal networks from hyperactivation in response to epileptogenic stimuli [34]. Given that some main hubs of PPIN are closely related to epilepsy, they are likely to be important molecules regulated by CZD in treatment of epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Uncovering the Pharmacological Mechanism ofChaibei ZhixianDecoction on Epilepsy by Network Pharmacology Analysis

Zhang

Zheng

Yuan

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Objective. Epilepsy is a neuronal disorder that is characterized by epileptic seizures and linked with abnormal neural functioning in the brain. Traditional Chinese medicine (TCM) formula Chaibei Zhixian decoction (CZD) has been widely used for epilepsy in China while the pharmacological mechanisms are still unclear. In the present study, systematic and comprehensive network pharmacology was utilized for the first time to reveal the potential pharmacological mechanisms of CZD on epilepsy. Methods. Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform was utilized for the development of an ingredients-targets database. After identifying epileptic targets of CZD, their interaction with other proteins was estimated based on protein-protein interaction network created from STITCH and gene ontology (GO) enrichment analysis utilizing Cytoscape-ClueGO plugin. Results. CZD formula was found to have 643 chemical ingredients, and the potential protein targets of these ingredients were 5230, as retrieved from TCMSP database. Twenty-six protein targets were found to be associated with epilepsy. Thirteen hub genes were regulated by CZD in epilepsy, including estradiol, ESR1, ESR2, SRC, CTNNB1, EP300, MAPK1, MAPK3, SP1, BRCA1, NCOA3, CHRM1, and GSK3B. The results of GO terms analysis showed that 8 GO terms were recovered in the form of 3 clusters, including negative regulation of protein kinase B signaling, positive regulation of interleukin-1 production, and microvillus assembly. Conclusions. Network pharmacology approach provides better understanding of the underlying pharmacological mechanisms of CZD on epilepsy. Estradiol, ESR1, ESR2, CTNNB1, EP300, MAPK1, MAPK3, BRCA1, and GSK3B are likely to be important molecules regulated by CZD in treatment of epilepsy. Negative regulation of protein kinase B signaling may play vital roles in the treatment of epilepsy by CZD.

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“…Mean gray values of every other sample are presented as ratios. Quantitative analysis of S6, Akt, and GluA1 phosphorylation levels was performed using the Infrared Odyssey Imaging System (LI-COR Biosciences) described previously (Urbanska et al, 2018, Urbanska et al, 2019).…”

Section: Methodsmentioning

confidence: 99%

“…Following incubation, they were washed three times for 10 min each in TBST and then incubated for 1.5-2 h in HRP-conjugated secondary antibody diluted in 2.5% milk in TBST. Finally, blots were developed for ~2-3 min in a freshly made chemiluminescence developing buffer (100 mM Tris phosphorylation levels was performed using the Infrared Odyssey Imaging System (LI-COR Biosciences) described previously (Urbanska et al, 2018, Urbanska et al, 2019.…”

Section: Western Blotmentioning

confidence: 99%

Rab11 regulates autophagy at dendritic spines in an mTOR- and NMDA-dependent manner

Janusz-Kaminska

Brzozowska

Tempes

et al. 2022

Preprint

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Synaptic plasticity is a process that shapes neuronal connections during neurodevelopment, learning, and memory. Autophagy is a mechanism that allows cells to degrade their unnecessary or dysfunctional components. Autophagosomes appear at dendritic spines in response to plasticity-inducing stimuli. Autophagy defects contribute to altered dendritic spine development, autistic-like behavior in mice, and neurological disease. While several studies explored the involvement of autophagy in synaptic plasticity, the steps preceding autophagosome emergence at the postsynapse remain unknown. Here we show a postsynaptic association of autophagy-related protein 9A (Atg9A), known to be involved in the initial stages of autophagosome formation, with Rab11, a small GTPase that regulates endosomal trafficking. Rab11 activity is necessary for the maintenance of Atg9A-positive structures at dendritic spines. Inhibition of mTOR increased Rab11 and Atg9A interaction and increased the emergence of autophagosomes in dendritic spines when coupled to NMDA receptor stimulation. Dendritic spines with newly formed autophagosomes were more resistant to NMDA-induced morphologic change. These results collectively suggest that autophagy initiation in dendritic spines depends on an activity-dependent Rab11a-Atg9A interaction regulated by mTOR.

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GSK3β Activity Alleviates Epileptogenesis and Limits GluA1 Phosphorylation

Cited by 4 publications

References 4 publications

Brain glycogen content is increased in the acute and interictal chronic stages of the mouse pilocarpine model of epilepsy

Brain glycogen content is increased in the acute and interictal chronic stages of the mouse pilocarpine model of epilepsy

Uncovering the Pharmacological Mechanism ofChaibei ZhixianDecoction on Epilepsy by Network Pharmacology Analysis

Rab11 regulates autophagy at dendritic spines in an mTOR- and NMDA-dependent manner

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