Neuronal dysfunction in the epileptic brain originating from glial cells

Abstract

In the complex field of epilepsy, glial cells are emerging as key players. Here, I present our findings on the role of microglia and astrocytes in specific epileptic conditions, exploring their mechanisms of action and potential therapeutic implications.　First, we examined auditory dysfunction reported in patients with temporal lobe epilepsy (TLE). Although increased neuronal activity has been observed in auditory pathways, including the primary auditory cortex and medial geniculate body (MGB), the cellular underpinnings remain elusive. Using a mouse model that mimics TLE after status epilepticus we identified the role of microglia in the disinhibition of these pathways. Over an 8-week period after status epilepticus, microglia were found to reduce inhibitory synapses on MGB relay neurons, catalyzing hyperactivity in auditory pathways. Interestingly, local removal of microglia from the MGB reduced this hyperactivity and restored auditory discrimination. This sheds light on the central role of thalamic microglia in epilepsy-induced auditory dysfunction.　On another front, we investigated the role of astrocytes in mesial temporal lobe epilepsy (MTLE), a challenging form of epilepsy characterized by hippocampal seizures. Using transcriptome analysis in an MTLE mouse model, we identified a significant increase in insulin-like growth factor binding protein 2 (Igfbp2) levels within gliosis-associated astrocytes. Preliminary results suggest that astrocytic Igfbp2 may be instrumental in driving epileptogenesis, providing a promising therapeutic avenue for the treatment of MTLE.　Taken together, these findings underscore the critical influence of glial cells in epilepsy and open avenues for novel therapeutic interventions targeting these cell types.