Astrocytes in Genetic Epilepsies: Supporting Actor or Key Player?

Epilepsy is one of the most common neurological disorders worldwide, affecting around 1% of the population. The epilepsies represent a diverse group of conditions, ranging from acquired forms resulting from neurological insults to common multifactorial epilepsies and rare, often monogenic epilepsies caused by highly penetrant genetic variants. The genetic epilepsies demonstrate frequent comorbidity with a range of neurodevelopmental and psychiatric disorders, and epileptic seizures are also a common feature of neurodevelopmental disorders such as Fragile X syndrome and Rett syndrome. Astrocytes, the most numerous glial cells in the central nervous system, have emerged as crucial players in the pathophysiology of acquired epilepsies. Whilst the contribution of astrocytes to acquired epilepsy has been widely reviewed, astrocyte dysfunction in rare genetic epilepsies or neurodevelopmental disorders has been neglected, despite the fact that the genes implicated are expressed in astrocytes, albeit to a lesser extent than in neurons. Additionally, affected individuals with rare genetic epilepsies are more likely to exhibit drug-resistant seizures, highlighting the need to identify novel therapeutic targets. In this paper, we review the existing literature on astrocyte dysfunction in genetic epilepsy syndromes and neurodevelopmental disorders with seizures. We have identified several key studies that highlight alterations in crucial astrocyte functions including calcium signaling and ion homeostasis. Our review highlights the need for further research to establish the contribution of astrocyte dysfunction to neuronal health and seizure activity in rare genetic epilepsies.