Constitutive deletion of astrocytic connexins aggravates kainate‐induced epilepsy

Abstract

The astroglial gap junctional network formed by connexin (Cx) channels plays a central role in regulating neuronal activity and network synchronization. However, its involvement in the development and progression of epilepsy is not yet understood. Loss of interastrocytic gap junction (GJ) coupling has been observed in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy (MTLE) and in mouse models of MTLE, leading to the suggestion that it plays a causative role in the pathogenesis. To further elucidate this clinically relevant question, we investigated consequences of astrocyte disconnection on the time course and severity of kainate‐induced MTLE with hippocampal sclerosis (HS) by comparing mice deficient for astrocytic Cx proteins with wild‐type mice (WT). Continuous telemetric EEG recordings and video monitoring performed over a period of 4 weeks after epilepsy induction revealed substantially higher seizure and interictal spike activity during the chronic phase in Cx deficient versus WT mice, while the severity of status epilepticus was not different. Immunohistochemical analysis showed that, despite the elevated chronic seizure activity, astrocyte disconnection did not aggravate the severity of HS. Indeed, the extent of CA1 pyramidal cell loss was similar between the experimental groups, while astrogliosis, granule cell dispersion, angiogenesis, and microglia activation were even reduced in Cx deficient as compared to WT mice. Interestingly, seizure‐induced neurogenesis in the adult dentate gyrus was also independent of astrocytic Cxs. Together, our data indicate that constitutive loss of GJ coupling between astrocytes promotes neuronal hyperexcitability and attenuates seizure‐induced histopathological outcomes.

The complement C3‐C3aR pathway mediates microglia–astrocyte interaction following status epilepticus

“…Extensive activation of microglia and astrocytes is observed in animal models of epilepsy and in cerebral tissues resected from epileptic patients (Eyo, Murugan, & Wu, 2017; Feng et al, 2019; Patel, Tewari, Chaunsali, & Sontheimer, 2019; Shapiro, Wang, & Ribak, 2008). Gliosis results from activation of microglia and astrocytes in response to CNS damage and ultimately leads to glial scar formation (Bedner et al, 2015; Deshpande et al, 2020; Sofroniew & Vinters, 2010; Szalay et al, 2016). Gliosis can be beneficial, by helping maintain the extracellular environment and restoring blood–brain barrier function, or detrimental by increasing regional concentrations of neurotoxic inflammatory substances, impairing functional recovery, and worsening clinical signs (Sofroniew, 2009; Zhang, Hu, Qian, O'Callaghan, & Hong, 2010).…”

Neuron-Glia Interactions in Neurodevelopmental Disorders

“…The gap junction is one of the crucial proteins in astrocytes for communication and forming the astrocytic syncytium. In a kainic acid (KA)-induced epilepsy model, astrocytic connexins were shown to aggravate epileptic signals [ 118 ]. In addition, inflammatory cytokines inhibit astrocyte gap junction coupling in cell culture experiments.…”

Astrocytic Connexin43 Channels as Candidate Targets in Epilepsy Treatment

“…Spontaneous seizure-like discharges induced by Mg 2+ -free solution recorded in the CA1 stratum pyramidale occurred with shorter latency and higher frequency in dKO slices [ 124 ]. Cx30/Cx43 dKO mice were subjected to an in vivo kainic acid MTLE model and, despite having a similar severity of SE as their wild type littermates, displayed a higher frequency of spontaneous generalized chronic seizures, supporting the view that loss of astrocyte coupling represents a crucial event in epileptogenesis [ 128 ].…”