FMRP(1–297)-tat restores ion channel and synaptic function in a model of Fragile X syndrome

Xiaoqin Zhan, Hadhimulya Asmara, Ning Cheng, Giriraj Sahu, Eduardo Sanchez, Fang-Xiong Zhang, Gerald W. Zamponi, Jong M. Rho and Ray W. Turner ()
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Xiaoqin Zhan: University of Calgary
Hadhimulya Asmara: University of Calgary
Ning Cheng: University of Calgary
Giriraj Sahu: University of Calgary
Eduardo Sanchez: University of Calgary
Fang-Xiong Zhang: University of Calgary
Gerald W. Zamponi: University of Calgary
Jong M. Rho: University of Calgary
Ray W. Turner: University of Calgary

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Fragile X Syndrome results from a loss of Fragile X Mental Retardation Protein (FMRP). We now show that FMRP is a member of a Cav3-Kv4 ion channel complex that is known to regulate A-type potassium current in cerebellar granule cells to produce mossy fiber LTP. Mossy fiber LTP is absent in Fmr1 knockout (KO) mice but is restored by FMRP(1-297)-tat peptide. This peptide further rapidly permeates the blood-brain barrier to enter cells across the cerebellar-cortical axis that restores the balance of protein translation for at least 24 h and transiently reduces elevated levels of activity of adult Fmr1 KO mice in the Open Field Test. These data reveal that FMRP(1-297)-tat can improve function from the levels of protein translation to synaptic efficacy and behaviour in a model of Fragile X syndrome, identifying a potential therapeutic strategy for this genetic disorder.

Date: 2020
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DOI: 10.1038/s41467-020-16250-4

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