Postnatal Activation of TLR4 in Astrocytes Promotes Excitatory Synaptogenesis in Hippocampal Neurons

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2016 Dec 7

PMID 27920126

Citations 64

Authors

Yi Shen

Huaping Qin

Juan Chen

Lingyan Mou

Yang He

Yixiu Yan

Hang Zhou

Ya Lv

Zhong Chen

Junlu Wang

Yu-Dong Zhou

Affiliations

Soon will be listed here.

Abstract

Astrocytes are critical in synapse development, and their dysfunction in crucial developmental stages leads to serious neurodevelopmental diseases, including seizures and epilepsy. Immune challenges not only affect brain development, but also promote seizure generation and epileptogenesis, implying immune activation is one of the key factors linking seizures and epilepsy to abnormal brain development. In this study, we report that activating astrocytes by systemic lipopolysaccharide (LPS) challenges in the second postnatal week promotes excitatory synapse development, leading to enhanced seizure susceptibility in mice. Toll-like receptor 4 (TLR4) activation in astrocytes increased astrocytic extracellular signal-related kinase 1/2 (Erk1/2) and phospho-Erk1/2 levels in a myeloid differentiation primary response protein 88 (MyD88)-dependent manner. Constitutively activating Erk1/2 in astrocytes was sufficient to enhance excitatory synaptogenesis without activating TLR4. Deleting MyD88 or suppressing Erk1/2 in astrocytes rescued LPS-induced developmental abnormalities of excitatory synapses and restored the enhanced seizure sensitivity. Thus, we provide direct evidence for a developmental role of astrocytes in shaping a predisposition to seizure generation.

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