Epilepsy Characteristics in Neurodevelopmental Disorders: Research from Patient Cohorts and Animal Models Focusing on Autism Spectrum Disorder

Abstract

Epilepsy, a heterogeneous group of brain-related diseases, has continued to significantly burden society and families. Epilepsy comorbid with neurodevelopmental disorders (NDDs) is believed to occur due to multifaceted pathophysiological mechanisms involving disruptions in the excitation and inhibition (E/I) balance impeding widespread functional neuronal circuitry. Although the field has received much attention from the scientific community recently, the research has not yet translated into actionable therapeutics to completely cure epilepsy, particularly those comorbid with NDDs. In this review, we sought to elucidate the basic causes underlying epilepsy as well as those contributing to the association of epilepsy with NDDs. Comprehensive emphasis is put on some key neurodevelopmental genes implicated in epilepsy, such as MeCP2, SYNGAP1, FMR1, SHANK1-3 and TSC1, along with a few others, and the main electrophysiological and behavioral deficits are highlighted. For these genes, the progress made in developing appropriate and valid rodent models to accelerate basic research is also detailed. Further, we discuss the recent development in the therapeutic management of epilepsy and provide a briefing on the challenges and caveats in identifying and testing species-specific epilepsy models.

Keywords: Fmr1; Mecp2; Scna1; Shank; Syngap1; Tsc1/2; autism spectrum disorder; biomarkers; electroencephalography; epilepsy.

Figure 1

Common pathophysiological features of epilepsy in genes implicated in human NDDs. Diagram illustrating neurodevelopmental phenotypes, predominant seizure types, and electroencephalographic hallmark characteristic features observed in patient cohorts of neurodevelopmental disorders. ASD/ID, autism spectrum disorder/intellectual disability; FMR1, fragile X mental retardation protein 1; TSC1/2, tuberous sclerosis complex 1/2; SHANK1-3, SH3 and multiple ankyrin repeat domains 1-3; MeCP2, methyl CpG binding protein 2; SYNGAP1, synaptic Ras-GTPase activating protein rat homolog 1.

Figure 2

Common pathophysiological features of epilepsy in animal genetic models associated with NDDs. Diagram illustrating neurodevelopmental phenotypes, predominant seizure types, and electroencephalographic hallmark characteristic features observed in genetically developed mouse models of neurodevelopmental disorders displaying epileptic phenotypes.

Figure 3

Species-specific differences in the intrinsic properties of astrocytes, neurons, and microglia. Apart from being larger in diameter and exhibiting extensive primary processes, hominid astrocytes display more resistance to oxidative stress, increased velocity of calcium propulsion, absence of enrichment in hypoxia-induced transcriptomic signatures of neural repair, inflammation-induced expression of antigen presentation genes, and resting state metabolism of mitochondria. Hominid features of morphologically complex, diverse, and larger neurons exhibit differential basal membrane properties, fewer channels, and lower ionic conductance per volume compared to rodent counterparts. Human microglia express some intrinsic gene signatures (not present in rodent microglia) such as the presence of CARD8, an inflammasome component; and granulysin, which is present in cytokine granules. Additionally, the ageing-related genes are oppositely misregulated in a species-dependent manner. Created with BioRender.com.