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

• Published in: Nature communications Vol. 11; no. 1; p. 2755
• Main Authors: Zhan, Xiaoqin, Asmara, Hadhimulya, Cheng, Ning, Sahu, Giriraj, Sanchez, Eduardo, Zhang, Fang-Xiong, Zamponi, Gerald W., Rho, Jong M., Turner, Ray W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.06.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14; 14/33; 631/378/2591; 64/110; 64/60; 692/699/375/366; 82/80; 9/74; 96; Animals; Blood-brain barrier; Brain - pathology; Cerebellar plasticity; Cerebellum; Disease Models, Animal; Field tests; FMR1 protein; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X syndrome; Fragile X Syndrome - genetics; Fragile X Syndrome - metabolism; Fragile X Syndrome - pathology; Genetic disorders; Granule cells; Humanities and Social Sciences; Intellectual disabilities; Ion channels; Ion Channels - metabolism; Long-term potentiation; Male; Mice; Mice, Knockout; multidisciplinary; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - metabolism; Neurodevelopmental Disorders - pathology; Neuronal Plasticity - genetics; Neuronal Plasticity - physiology; Neurons - metabolism; Open-field behavior; Peptides; Potassium; Protein Biosynthesis; Proteins; Rodents; Science; Science (multidisciplinary); Synaptic plasticity; Synaptic strength; Translation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16250-4

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. Fragile X Mental Retardation Protein regulates synaptic plasticity and its loss results in Fragile X Syndrome. Here, the authors show that the FMRP(1-297)- tat peptide can permeate the BBB, restore protein translation and mossy fiber LTP, and reduce elevated levels of activity in Fmr1 KO mice.