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Sonic hedgehog is a regulator of extracellular glutamate levels and epilepsy
Author(s) -
Feng Shengjie,
Ma Shaorong,
Jia Caixia,
Su Yujuan,
Yang Shenglian,
Zhou Kechun,
Liu Yani,
Cheng Ju,
Lu Dunguo,
Fan Liu,
Wang Yizheng
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201541569
Subject(s) - sonic hedgehog , glutamate receptor , microbiology and biotechnology , epileptogenesis , morphogen , biology , extracellular , neuroscience , epilepsy , chemistry , signal transduction , biochemistry , receptor , gene
Sonic hedgehog (Shh), both as a mitogen and as a morphogen, plays an important role in cell proliferation and differentiation during early development. Here, we show that Shh inhibits glutamate transporter activities in neurons, rapidly enhances extracellular glutamate levels, and affects the development of epilepsy. Shh is quickly released in response to epileptic, but not physiological, stimuli. Inhibition of neuronal glutamate transporters by Shh depends on heterotrimeric G protein subunit Gα i and enhances extracellular glutamate levels. Inhibiting Shh signaling greatly reduces epileptiform activities in both cell cultures and hippocampal slices. Moreover, pharmacological or genetic inhibition of Shh signaling markedly suppresses epileptic phenotypes in kindling or pilocarpine models. Our results suggest that Shh contributes to the development of epilepsy and suppression of its signaling prevents the development of the disease. Thus, Shh can act as a modulator of neuronal activity, rapidly regulating glutamate levels and promoting epilepsy.