Astrocytes as a target for therapeutic strategies in epilepsy: current insights

Abstract

Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission). Astrocytes play a key roles in epileptogenesis and seizure generation. Epilepsy, as a chronic disorder characterized by neuronal hyperexcitation and hypersynchronization, is accompanied by substantial disturbances of glial cells and impairment of astrocytic functions and neuronal signaling. Anti-seizure drugs that provide symptomatic control of seizures primarily target neural activity. In epileptic patients with inadequate control of seizures with available anti-seizure drugs, novel therapeutic candidates are needed. These candidates should treat epilepsy with anti-epileptogenic and disease-modifying effects. Evidence from human and animal studies shows that astrocytes have value for developing new anti-seizure and anti-epileptogenic drugs. In this review, we present the key functions of astrocytes contributing to neuronal hyperexcitability and synaptic activity following an etiology-based approach. We analyze the role of astrocytes in both development (epileptogenesis) and generation of seizures (ictogenesis). Several promising new strategies that attempted to modify astroglial functions for treating epilepsy are being developed: (1) selective targeting of glia-related molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) gliotransmission; (4) targeting the astrocytic Kir4.1-BDNF system; (5) astrocytic Na+/K+/ATPase activity; (6) targeting DNA hypo- or hypermethylation of candidate genes in astrocytes; (7) targeting astrocytic gap junction regulators; (8) targeting astrocytic adenosine kinase (the major adenosine-metabolizing enzyme); and (9) targeting microglia-astrocyte communication and inflammatory pathways. Novel disease-modifying therapeutic strategies have now been developed, such as astroglia-targeted gene therapy with a broad spectrum of genetic constructs to target astroglial cells.

Transcriptomic alterations in cortical astrocytes following the development of post-traumatic epilepsy

“…Dysregulation of astrocytes has been implicated in the development and progression of epilepsy 11 , 12 . Understanding how the transcriptomic landscape is altered in astrocytes will uncover key molecular pathways and reveal potential therapeutic targets to prevent the development of PTE.…”

YY1 mutations disrupt corticogenesis through a cell-type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs

“…Therefore, we established a website to collect detailed phenotypic data of individuals harboring YY1 mutations not only to gain insight into the clinical spectrum that these mutations might cause but also to obtain fundamental understanding of the pathogenic mechanisms underlying the Gabriele-de Vries syndrome (https://humandiseasegenes.nl/yy1). With this first modelling of GADEVS, we provide a high-resolution definition of its key pathogenic mechanisms, uncovering multiscale longitudinal phenotypes, cell-autonomous and non-cell autonomous alike, whose multiomic underpinnings and functional readouts orient the search for druggable targets and repurposed compounds in physio-pathologically relevant human neuronal lineages 60–62 .…”

Epilepsy-related functional brain network alterations are already present at an early age in the GAERS rat model of genetic absence epilepsy

“…Enhanced manganese accumulation was observed during post-stroke inflammatory processes and was associated with activated microglia and reactive astrocytes ( 69 ). Neuronal loss as a prerequisite of local brain inflammation was not found in GAERS ( 70 ), but reactive astrogliosis coupled with altered cytokine expression has been observed in GAERS and was linked to epileptogenesis ( 71 ).…”