Epileptogenesis mediated by glial cells

Abstract

Epilepsy is one of the most common diseases of the central nervous system. Many epilepsies are controllable because of the existence of different antiepileptic drugs with multiple mechanisms of action. However, about 30% of epilepsy is so-called refractory epilepsy in which existing drugs do not show enough therapeutic effects. Antiepileptic drugs can be roughly divided into two types, i.e., those that suppress the excitability of neuronal cells and those that promote inhibition. Inhibition of excitatory neurons include a variety of ion channel inhibitors such as Na⁺, drugs that inhibit glutamate release and glutamate AMPA receptor, whereas enhancement of inhibitory neurons includes a drug that enhances GABA_A receptor. Both are targeted to neurons. Recent advances in brain science have revealed the importance of the role of glial cells in regulation of brain function and excitability of neurons. Although glia cells themselves are electrically non-excitable cells, they could greatly affect excitability of neurons by controlling extracellular neurotransmitters, glial transmitters, regulating various ions concentration, regulation of energy metabolism, and formation/elimination of synapses. Therefore, when the function of glial cells changes, these regulatory functions also change, which in turn greatly changes the excitability of neurons and neuronal networks. Epilegenicity is a condition in which the brain is likely to undergo spontaneous epileptic seizures and it is suggested that modulation of the above-mentioned glial cell function is greatly related to the acquisition of epileptogenesis. In this article, I focus on astrocytes among glial cells, and describe the relationship between functional modulation and epileptogenesis when changing to the phenotype of reactive astrocytes by epileptic seizures. We also discuss development of antiepileptic drugs targeting reactive astrocytes.