Sonic hedgehog is a regulator of extracellular glutamate levels and epilepsy.
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 Gαi 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.
Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China University of Chinese Academy of Sciences, Shanghai, China.
Shengjie
S
Feng
Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China University of Chinese Academy of Sciences, Shanghai, China.
Shaorong
S
Ma
Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Caixia
C
Jia
Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China University of Chinese Academy of Sciences, Shanghai, China.
Yujuan
Y
Su
Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Shenglian
S
Yang
Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Kechun
K
Zhou
Center of Cognition and Brain Science, AMMS, Beijing, China.
Yani
Y
Liu
Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China University of Chinese Academy of Sciences, Shanghai, China.
Ju
J
Cheng
Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Dunguo
D
Lu
Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Liu
L
Fan
Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China yzwang@ion.ac.cn.
Yizheng
0000-0002-9214-2596
Y
Wang
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism*; D005110:Extracellular Space; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D018698:Glutamic Acid / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism
D053823:Hedgehog Proteins; D000071676:Zinc Finger Protein GLI1; D018698:Glutamic Acid; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium
Epilepsy; extracellular glutamate; glutamate transporter; neuronal activity; sonic hedgehog