TY - JOUR
T1 - Elevated erk/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in Fragile X mice
AU - Sawicka, Kirsty
AU - Pyronneau, Alexander
AU - Chao, Miranda
AU - Bennett, Michael V.L.
AU - Zukin, R. Suzanne
N1 - Funding Information:
We thank Fabrizio Pontarelli and Brenda Court-Vasquez for technical assistance and Dr. Jingqi Yan for invaluable advice. We thank members of the R.S.Z. laboratory for helpful comments and suggestions on the manuscript. This work was supported by NIH Grants MH092877 and NS45693, a McKnight Foundation Brain Disorders Award, a National Association for Research on Schizophrenia and Depression Distinguished Investigator Award from the Brain & Behavior Research Foundation, a generous grant from the F. M. Kirby Foundation (to R.S.Z.), and a FRAXA Research Foundation Postdoctoral Fellowship (to K.S.). R.S.Z. is the F. M. Kirby Professor in Neural Repair and Protection.
PY - 2016/10/11
Y1 - 2016/10/11
N2 - Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.
AB - Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.
KW - Autism
KW - FMRP
KW - Intellectual disability
KW - MTOR
KW - RSK
UR - http://www.scopus.com/inward/record.url?scp=84991435169&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84991435169&partnerID=8YFLogxK
U2 - 10.1073/pnas.1610812113
DO - 10.1073/pnas.1610812113
M3 - Article
C2 - 27663742
AN - SCOPUS:84991435169
SN - 0027-8424
VL - 113
SP - E6290-E6297
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 41
ER -