Control of neuronal excitability by GSK-3beta: Epilepsy and beyond

Jaworski, Tomasz

doi:10.1016/j.bbamcr.2020.118745

Cited by 23 publications

(15 citation statements)

References 232 publications

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“…Both GSK-3β and CDK5 play a role in neuronal excitability through involvement in GABAergic and glutamatergic neurotransmission, and inhibiting their activity can affect network activity through various mechanisms ( Sen et al, 2008 ; Jaworski, 2020 ; Toral-Rios et al, 2020 ; Banerjee et al, 2021 ). Therefore, inhibiting these kinases should be approached with caution.…”

Section: Dysregulation Of Cell Signaling Activity Upstream Of Tau Pho...mentioning

confidence: 99%

Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms

Hwang

Vaknalli

Addo-Osafo

et al. 2022

Front. Aging Neurosci.

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Tau is a microtubule-associated protein known to bind and promote assembly of microtubules in neurons under physiological conditions. However, under pathological conditions, aggregation of hyperphosphorylated tau causes neuronal toxicity, neurodegeneration, and resulting tauopathies like Alzheimer’s disease (AD). Clinically, patients with tauopathies present with either dementia, movement disorders, or a combination of both. The deposition of hyperphosphorylated tau in the brain is also associated with epilepsy and network hyperexcitability in a variety of neurological diseases. Furthermore, pharmacological and genetic targeting of tau-based mechanisms can have anti-seizure effects. Suppressing tau phosphorylation decreases seizure activity in acquired epilepsy models while reducing or ablating tau attenuates network hyperexcitability in both Alzheimer’s and epilepsy models. However, it remains unclear whether tauopathy and epilepsy comorbidities are mediated by convergent mechanisms occurring upstream of epileptogenesis and tau aggregation, by feedforward mechanisms between the two, or simply by coincident processes. In this review, we investigate the relationship between tauopathies and seizure disorders, including temporal lobe epilepsy (TLE), post-traumatic epilepsy (PTE), autism spectrum disorder (ASD), Dravet syndrome, Nodding syndrome, Niemann-Pick type C disease (NPC), Lafora disease, focal cortical dysplasia, and tuberous sclerosis complex. We also explore potential mechanisms implicating the role of tau kinases and phosphatases as well as the mammalian target of rapamycin (mTOR) in the promotion of co-pathology. Understanding the role of these co-pathologies could lead to new insights and therapies targeting both epileptogenic mechanisms and cognitive decline.

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Section: Dysregulation Of Cell Signaling Activity Upstream Of Tau Pho...mentioning

confidence: 99%

Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms

Hwang

Vaknalli

Addo-Osafo

et al. 2022

Front. Aging Neurosci.

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“…Several studies have also identified a role for glycogen synthase kinase-3 (GSK3) in regulating Na v 1.6 activity. Beyond regulation of glycogen metabolism, this kinase plays important roles in the regulation of neuronal development and function, including synaptic plasticity and neuronal excitability [ 223 , 224 , 225 ]. A previous report demonstrated that pharmacological inhibition and genetic silencing of GSK3β produces loss-of-function effects on channel activity, resulting in decreased transient and persistent Na v 1.6 sodium currents in addition to a leftward shift in channel availability [ 226 ].…”

Section: Post-translational Regulation Of Na V 16mentioning

confidence: 99%

Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

Zybura

Hudmon

Cummins

2021

Cells

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Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Nav1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Nav1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Nav1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav isoforms, others are isoform-specific. Additionally, considerable progress has been made toward understanding how individual protein interactions and/or modifications affect Nav1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Nav1.6 in neuronal function and provide a thorough review of this channel’s complex regulatory mechanisms and how they may contribute to neuromodulation.

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“…Although not measured, like in previous studies, 37,38 we expect lower GSK3β activity and inhibition of GSK3β at the phosphorylation level. GSK3β controls neuronal excitability by regulating the expression and activity of voltage-gated sodium, potassium, and calcium channels, and glutamatergic and GABAergic receptors (reviewed in 39 ). However, there is no consensus about the extent and how GSK3β function alters seizure susceptibility.…”

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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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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Control of neuronal excitability by GSK-3beta: Epilepsy and beyond

Cited by 23 publications

References 232 publications

Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms

Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms

Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

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

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