The Effect And Mechanism Of Astrocyte Activation On Immune Challenge-induced Seizure Susceptibility In Juvenile Mice

The highest incidence of seizures occurs in early life,suggesting that seizure activities may be related to deficits in brain development.Plenty of predisposing risk factors during development,such as immune challenges,not only affect brain development,but also promote seizure generation,suggesting immune activation is one of the key factors linking seizures and epilepsy to abnormal brain development.Astrocyte,a major glial cell type in the brain,actively regulates neuronal development.Disrupting astrocyte activities and functions in crucial developmental stages leads to serious neurodevelopmental dysfunctions,including seizures and epilepsy.In addition,the pattern recognition receptor Toll-like receptor 4(TLR4)is expressed in astrocytes and has shown to be involved in epileptogenesis.However,the effect and mechanism of astrocytic TLR4 activation on neuronal and synapse development and seizure susceptibility in young mice remain to be elucidated.Here 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 ERK1/2 and phospho-ERKl/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.