Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis

Lee, Wei Shern; Baldassari, Sara; Stephenson, Sarah E. M.; Lockhart, Paul J.; Baulac, Stéphanie; Leventer, Richard J.

doi:10.3390/ijms23031344

Cited by 17 publications

(12 citation statements)

References 115 publications

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“…1–3 ) 9,26 . Dysregulation of the mTORC1 pathway leads to defects in migration of neural progenitors and cellular and circuit abnormalities 1 . We extend the characterization of the RHEB CA mouse model by showing that it has significant impairments in working memory and social recognition ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Focal Cortical Dysplasia (FCD) is a malformation of cortical development (MCD) and is among the leading causes of drug-resistant focal epilepsy 1 pathology found in children undergoing epilepsy surgery 2 . Because tissue is required to confirm the diagnosis, precise estimates of the prevalence are not available.…”

Section: Introductionmentioning

confidence: 99%

“…FCD type II (FCD II) is characterized by dyslamination and dysmorphic neurons in a restricted area of the cortex and is generally caused by somatic mutations in neural progenitors 4 . Approximately 60% of FCD II lesions are caused by mutations affecting the mTORC1 (mammalian Target of Rapamycin Complex 1) signalling pathway 1 . Despite advances in the molecular defects underlying FCD II, the mechanisms leading to seizures are incompletely understood 1 , as are the circuit disorders underlying cognitive and behavioural comorbidities that are frequently seen in affected children.…”

Section: Introductionmentioning

confidence: 99%

“…Approximately 60% of FCD II lesions are caused by mutations affecting the mTORC1 (mammalian Target of Rapamycin Complex 1) signalling pathway 1 .…”

Section: Introductionmentioning

confidence: 99%

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Anti-seizure Gene Therapy for Focal Cortical Dysplasia

Barbanoj

Graham

Maffei

et al. 2023

Preprint

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Focal Cortical Dysplasias (FCDs) are a common subtype of malformation of cortical development, which frequently present with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. FCD type II is typically caused by somatic mutations resulting in mTOR hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe FCD. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established FCD model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human RHEB plasmid, an activator of mTOR Complex 1. First, we further characterised this by quantifying electrocorticograms and behavioural abnormalities, both in mice developing spontaneous generalised seizures and in mice only exhibiting abnormal interictal discharges. Then, using continuous video-electrocorticogram recordings from epileptic mice before and after injection of AAV9-CAMK2A-EKC in the dysplastic region, we observed a robust decrease in the frequency of seizures and in interictal activity, compared to mice injected with a control viral vector. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal activity or behaviour in non-epileptic mice. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Approximately 60% of FCD II lesions are caused by mutations affecting the mTORC1 (mammalian Target of Rapamycin Complex 1) signalling pathway 1 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Anti-seizure Gene Therapy for Focal Cortical Dysplasia

Barbanoj

Graham

Maffei

et al. 2023

Preprint

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“…Among others, mTOR, PI3K-Akt, p53, PTEN, MAPK pathways have been affected. Since these pathways are associated with brain disorders including epilepsy and genome stability maintenance [24,[100][101][102][103][104], somatic mosaicism and chromosome (genome) instability should become an important focus of cytogenomic epileptology.…”

Section: Preliminary Cytogenomic Analysis Of the Cohortmentioning

confidence: 99%

Cytogenomic epileptology

et al. 2023

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Molecular cytogenetic and cytogenomic studies have made a contribution to genetics of epilepsy. However, current genomic research of this devastative condition is generally focused on the molecular genetic aspects (i.e. gene hunting, detecting mutations in known epilepsy-associated genes, searching monogenic causes of epilepsy). Nonetheless, chromosomal abnormalities and copy number variants (CNVs) represent an important part of genetic defects causing epilepsy. Moreover, somatic chromosomal mosaicism and genome/chromosome instability seem to be a possible mechanism for a wide spectrum of epileptic conditions. This idea becomes even more attracting taking into account the potential of molecular neurocytogenetic (neurocytogenomic) studies of the epileptic brain. Unfortunately, analyses of chromosome numbers and structure in the affected brain or epileptogenic brain foci are rarely performed. Therefore, one may conclude that cytogenomic area of genomic epileptology is poorly researched. Accordingly, molecular cytogenetic and cytogenomic studies of the clinical cohorts and molecular neurocytogenetic analyses of the epileptic brain appear to be required. Here, we have performed a theoretical analysis to define the targets of the aforementioned studies and to highlight future directions for molecular cytogenetic and cytogenomic research of epileptic disorders in the widest sense. To succeed, we have formed a consortium, which is planned to perform at least a part of suggested research. Taking into account the nature of the communication, “cytogenomic epileptology” has been introduced to cover the research efforts in this field of medical genomics and epileptology. Additionally, initial results of studying cytogenomic variations in the Russian neurodevelopmental cohort are reviewed with special attention to epilepsy. In total, we have concluded that (i) epilepsy-associated cytogenomic variations require more profound research; (ii) ontological analyses of epilepsy genes affected by chromosomal rearrangements and/or CNVs with unraveling pathways implicating epilepsy-associated genes are beneficial for epileptology; (iii) molecular neurocytogenetic (neurocytogenomic) analysis of postoperative samples are warranted in patients suffering from epileptic disorders.

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