Foxp3 exhibits antiepileptic effects in ictogenesis involved in TLR4 signaling

Inflammatory processes play critical roles in epileptogenesis, but the exact mechanisms that underlie these processes are still not completely understood. In this study, we investigated the role of forkhead transcription factor 3 (Foxp3), a transcription factor that is involved in T-cell differentiation, in epileptogenesis. In both human epileptic tissues and experimental seizure models, we found significant up-regulation of Foxp3 in neurons and glial cells. Of importance, Foxp3^-/- mice were susceptible to kainic acid-induced seizures, whereas overexpression of Foxp3 reduced acute seizure occurrence and decreased chronic seizure recurrence. In addition, in vitro experiments revealed that Foxp3 inhibited neuronal excitability via glial cells and not neurons. The protective effects of Foxp3 were manifested as a reduction in glial cell activation and proinflammatory cytokine production and increased neuronal survival. Moreover, we showed that beneficial effects of Foxp3 involved the attenuation of TLR4 signaling and inflammation, which led to the inactivation of NR2B-containing NMDA receptors. These results suggest that Foxp3 in glial cells may play an antiepileptic role in epileptogenesis and may act as a modulator of TLR4. Taken together, our results indicate that Foxp3 may represent a novel therapeutic target for achieving anticonvulsant effects in patients with epilepsy that is currently resistant to drugs.-Wang, F.-X., Xiong, X.-Y., Zhong, Q., Meng, Z.-Y., Yang, H., Yang, Q.-W. Foxp3 exhibits antiepileptic effects in ictogenesis involved in TLR4 signaling.