Acute inhibition of the STA3 signaling pathway during epileptogenesis prevent GABAergic cells’ loss and imprinting of epileptic state: an in-vitro proof

Abstract

ABSTRACTEpilepsy, the condition of recurrent unprovoked seizures resulting from a wide variety of causes, is one of the world’s most prominent brain syndrome. Seizures which are an expression of neuronal network dysfunction occur in a positive feedback loop of concomitant factors where seizures generate more seizures, including also neuro-inflammatory responses. Among other pathways involved in inflammatory responses, the JAK/STAT signaling pathway has been proposed to prevent epilepsy. In this work we tested on a model of temporal lobe epilepsy in-vitro, the hypothesis that acute inhibition of STAT3-phosphorylation - during epileptogenesis, can prevent structural damages in the hippocampal circuits, and the imprinting both of neural epileptic activity and inflammatory glial states. We performed calcium imaging of spontaneous circuits’ dynamics in organotypic hippocampal slices previously exposed to hyper-excitable conditions through the blockage of GABAergic synaptic transmission. Epileptogenic conditions lead to imprinted epileptic dynamics in the circuits in terms of higher frequency of neuronal firing and circuits’ synchronizations, higher correlated activity in neuronal pairs and decreased complexity in synchronization patterns. Acute inhibition of the STAT3-phosphorylation during epileptogenesis, prevented the imprinting of epileptic activity patterns, general cell loss, GABAergic cells’ loss and the persistence of inflammatory reactive glial states. This work provides further evidence that inhibiting the STAT3 signaling pathway under epileptogenesis can prevent patho-topological reorganization of neuro-glial circuits.