Microglia as a Game Changer in Epilepsy Comorbid Depression

As one of the most common neurological diseases, epilepsy is often accompanied by psychiatric disorders. Depression is the most universal comorbidity of epilepsy, especially in temporal lobe epilepsy (TLE). Therefore, it is urgently needed to figure out potential mechanisms and the optimization of therapeutic strategies. Microglia play a pivotal role in the coexistent relationship between epilepsy and depression. Activated microglia released cytokines like IL-6 and IL-1β, orchestrating neuroinflammation especially in the hippocampus, worsening both depression and epilepsy. The decrease of intracellular K+ is a common part in various molecular changes. The P2X7-NLRP3-IL-1β is a major inflammatory pathway that disrupts brain network. Extra ATP and CX3CL1 also lead to neuronal excitotoxicity and blood-brain barrier (BBB) disruption. Regulating neuroinflammation aiming at microglia-related molecules is capable of suspending the vicious mutual aggravating circle of epilepsy and depression. Other overlaps between epilepsy and depression lie in transcriptomic, neuroimaging, diagnosis and treatment. Hippocampal sclerosis (HS) and amygdala enlargement (AE) may be the underlying macroscopic pathological changes according to current studies. Extant evidence shows that cognitive behavioral therapy (CBT) and antidepressants like selective serotonin-reuptake inhibitors (SSRIs) are safe, but the effect is limited. Improvement in depression is likely to reduce the frequency of seizure. More comprehensive experiments are warranted to better understand the relationship between them.