Dr. Yu-Dong Zhou's Group Uncover a Developmental Role of Astrocytes in Promoting Synapse Generation
2016-11-25 OnClick: 99
Prof. Yu-Dong Zhou, a principal investigator in the Institute of Neuroscience, and his colleagues demonstrate a developmental role of astrocytes in shaping a predisposition to seizure generation. Activation of TLR4-MyD88-ERK1/2 signaling pathway in astrocytes during a critical postnatal period promotes excitatory synapse generation, leading to enhanced seizure susceptibility. The results were published in The Journal Cell Biology on November 10, 2016 (DOI: 10.1083/jcb.201605046).
Astrocytes, a major class of glial cells in the central nervous system (CNS), actively regulate axon guidance, synapse formation and maturation, synapse function and plasticity, and neuronal survival during development. Disrupting astrocyte activities and functions in crucial developmental stages leads to serious neurodevelopmental dysfunctions, including seizures and epilepsy, autism, and Noonan syndrome. However, how pathologically activated astrocytes shape a predisposition to these dysfunctions remains to be elucidated. In addition, as a major class of immune cells in the brain, whether astrocytes affect central circuit wiring upon immune activation during development is an open scientific question in the fields of glial cell biology and developmental neurobiology.
In the current work, Dr. Zhou and his colleagues showed that peripheral immune challenges in juvenile mice induced astrocyte activation in the brain. This immune insults-induced activation of astrocytes promoted excitatory synapse generation in the hippocampus, causing increased seizure susceptibility in these juvenile mice. Dr. Zhou’s research team further depicted a crucial TLR4-MyD88-ERK1/2 pathway in astrocytes underpinning the peripheral immune challenge-induced enhancement of seizure susceptibility during postnatal development. Suppressing the TLR4-mediated pathway in astrocytes rescued the enhanced seizure sensitivity. This signaling pathway may also be relevant to CNS infection-induced seizures and epilepsy in children. Most infectious agents associated with childhood seizures and epilepsy are recognized by TLRs in a MyD88-dependent manner. Therefore, the MyD88-dependent ERK1/2 activation may serve as a common pathological mechanism for many immune activation-related diseases.
Drs. Yi Shen and Huaping Qin shared the co-first authorship. This work is supported by the Major Research Program from the State Ministry of Science and Technology of China, the National Natural Science Foundation of China, and the Zhejiang Provincial Natural Science Foundation of China.