Maladaptive myelination promotes epileptogenesis in absence epilepsy

Knowles, Juliet K.; Soane, Caroline; Frost, Eleanor; Tam, Lydia; Fraga, Danielle; Xu, Haojun; Batra, Ankita; Ni, Lijun; Villar, Katlin; Saucedo, Tristan; Huguenard, John R.; Monje, Michelle

doi:10.1101/2020.08.20.260083

Cited by 8 publications

(8 citation statements)

References 111 publications

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“…It is thought that dysregulation of either developmental or activity dependent myelination can contribute to status epilepticus onset and the progression to epilepsy, and that seizure itself can promote dysregulation of remyelination, increasing pathological circuit function that promotes further epileptic activity (Gibson, et al, 2017). Indeed, a recent paper has found that remyelination during epilepsy supported the recurrence of seizures, suggesting that remyelination is contributing to disease pathology over time (Knowles, et al, 2022). Our findings suggest that part of this mechanism may be due to the changes in neuron to OPC connections, which may be instructive for myelination, and are lost after seizure.…”

Section: Discussionsupporting

confidence: 52%

Adolescent Seizure Impacts Oligodendrocyte Development, Neuronal-Glial Circuit Formation, and Myelination

Foutch,

Tilton,

Cooney

et al. 2024

Preprint

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Myelin sheaths, formed by oligodendrocyte cells in the CNS, are vital for rapid conduction of electrical signals down neuronal axons. Oligodendrocyte progenitors differentiate and myelinate axons during development and following demyelinating injury. However, the mechanisms that drive the timing and specificity of developmental myelination are not well understood. It is known that oligodendrocyte progenitors receive synapses from neurons, providing a potential mechanism for neuronal-glial communication. We have previously shown that changing neuronal activity affects the proliferation of oligodendrocyte cells and neuron to OPC connections. We hypothesized that OPC proliferation and differentiation would be affected by pathological neuronal activity during adolescent development, when developmental myelination is occuring, and that this would also impact neuron to OPC connectivity and myelination. We used kainic acid to induce a seizure, then analyzed changes in the rate of OPC proliferation and differentiation five days later in the cerebral cortex, corpus callosum, and hippocampus. We found that OPC proliferation increased, the overall numbers of OPCs increased, and the number of mature oligodendrocytes decreased. We measured changes in the myelination to determine whether seizure activity directly affected myelination rate in adolescent development, and found decreased myelin in the cerebral cortex, corpus callosum, and hippocampus. We used viral monosynaptic circuit tracing to determine whether connections between neurons and OPCs were affected by seizure activity, and found a decrease in neuron to OPC connections in seizure mice compared to controls. Finally, we measured changes in the presence of kir4.1 potassium channels in OPCs, an important regulator of OPC membrane potential as well as an ion channel important for myelination, and found that there was a decrease in the number of potassium channels on OPCs after adolescent seizure. These findings provide insight into the response of the adolescent brain to seizure activity, as well as how seizures affect neuronal glial connections, OPC development and myelin formation, with the goal of understanding how these mechanisms may be important for treatment of demyelination after seizure and in epilepsy.

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Section: Discussionsupporting

confidence: 52%

Adolescent Seizure Impacts Oligodendrocyte Development, Neuronal-Glial Circuit Formation, and Myelination

Foutch,

Tilton,

Cooney

et al. 2024

Preprint

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“…Myelination deficiencies have been found in several neurologic disorders in particular in multiple sclerosis [41] and are often associated with seizure occurrence [42]. There is increasing awareness that also in epilepsy maladaptive myelination or axon demyelination are of high relevance for seizure generation [19,18].…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, Knowles et al [18] found increased oligodendrogenesis and myelination in an animal model for absence seizures and demonstrated that it contributes to epilepsy progression. In contrast, we found in our human FCD IIa cases thinner myelin sheaths in layer V/VI of the temporal lobe [24] and, as shown here, of the frontal lobe.…”

Section: Discussionmentioning

confidence: 99%

“…Correct myelination is very important for proper brain function and a highly dynamic process involved in memory consolidation in the adult brain [17]. There is recent evidence, that maladaptive myelination does also play a role in epileptic conditions [18,19]. Indeed, recent reports show a loss of oligodendrocytes (OL) and myelination capacity in the white matter of FCD lesions [14,20,21,22].…”

Section: Introductionmentioning

confidence: 99%

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Focal cortical dysplasia type II-dependent maladaptive myelination in the human frontal lobe

Donkels,

Huber,

Demerath

et al. 2024

Preprint

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Focal cortical dysplasias (FCDs) are local malformations of the human neocortex and a leading cause of intractable epilepsy. FCDs are classified into different subtypes including FCD IIa and IIb, characterized by a blurred gray-white matter boundary or a transmantle sign indicating abnormal white matter myelination. Recently, we have shown that myelination is also compromised in the gray matter of FCD IIa of the temporal lobe. Since myelination is key for brain function, we investigated whether deficient myelination is a feature affecting also other FCD subtypes and brain areas. Here, we focused on the gray matter of FCD IIa and IIb from the frontal lobe. We appliedin situhybridization, immunohistochemistry and electron microscopy to quantify oligodendrocytes, to visualize the myelination pattern and to determine ultrastructurally the axon diameter and the myelin sheath thickness. In addition, we analyzed the transcriptional regulation of myelin-associated transcripts by real-time RT-qPCR and chromatin immunoprecipitation (ChIP). We show that densities of myelinating oligodendrocytes and the extension of myelinated fibers up to layer II were unaltered in both FCD types but myelinated fibers appeared fractured mainly in FCD IIa. Interestingly, both FCD types presented with larger axon diameters when compared to controls. A significant correlation of axon diameter and myelin sheath thickness was found for FCD IIb and controls, whereas in FCD IIa large caliber axons were less myelinated. This was mirrored by a down-regulation of myelin-associated mRNAs and by reduced binding-capacities of the transcription factor MYRF to promoters of myelin-associated genes. FCD IIb, however, had significantly elevated transcript levels and MYRF-binding capacities reflecting the need for more myelin due to increased axon diameters. These data show that FCD IIa and IIb are characterized by divergent signs of maladaptive myelination which may contribute to the epileptic phenotype and underline the view of separate disease entities.

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“…neuronal over-excitation is considered an essential feature across different types of epileptic seizure models (Knowles et al, 2022). Thus, an improved understanding of the mechanisms underlying seizure progression, particularly neuronal overactivation, could facilitate the development of innovative anti-epileptogenic treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

Blocking salt‐inducible kinases with YKL‐06‐061 prevents PTZ‐induced seizures in mice

Peng,

Li,

Tang

et al. 2023

Brain and Behavior

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IntroductionEpilepsy is one of the most common neurological diseases, while over one third of adults with epilepsy still have inadequate seizure control. Although mutations in salt‐inducible kinases (SIKs) have been identified in epileptic encephalopathy, it is not known whether blocking SIKs can prevent pentylenetetrazole (PTZ)‐induced seizures.MethodsWe first determined the time course of SIKs (including SIK 1, 2, and 3) in the hippocampus of PTZ treated mice. And then, we evaluated the effects of anti‐epilepsy drug valproate acid (VPA) on the expression of SIK 1, 2, and 3 in the hippocampus of PTZ treated mice. Next, we investigated the effect of different dose of SIKs inhibitor YKL‐06‐061 on the epileptic seizures and neuronal activation by determining the expression of immediate early genes (IEGs) in the PTZ treated mice.ResultsWe found that PTZ selectively induced enhanced expression of SIK1 in the hippocampus, which was blocked by VPA treatment. Notably, YKL‐06‐061 decreased seizure activity and prevented neuronal overactivity, as indicated by the reduced expression of IEGs in the hippocampus and prefrontal cortex.ConclusionOur findings provide the first evidence that SIK1 affects gene regulation in neuronal hyperactivity, which is involved in seizure behavior. Targeting SIK1 through the development of selective inhibitors may lead to disease‐modifying therapies that reduce epilepsy progression.

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Maladaptive myelination promotes epileptogenesis in absence epilepsy

Cited by 8 publications

References 111 publications

Adolescent Seizure Impacts Oligodendrocyte Development, Neuronal-Glial Circuit Formation, and Myelination

Adolescent Seizure Impacts Oligodendrocyte Development, Neuronal-Glial Circuit Formation, and Myelination

Focal cortical dysplasia type II-dependent maladaptive myelination in the human frontal lobe

Blocking salt‐inducible kinases with YKL‐06‐061 prevents PTZ‐induced seizures in mice

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