Premium
c‐Jun N ‐terminal kinase regulates mG luR‐dependent expression of post‐synaptic FMRP target proteins
Author(s) -
Schmit Travis L.,
Dowell James A.,
Maes Margaret E.,
Wilhelm Michael
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12453
Subject(s) - fmr1 , metabotropic glutamate receptor , fragile x syndrome , long term potentiation , synaptic plasticity , microbiology and biotechnology , long term depression , neuroscience , kinase , biology , knockout mouse , glutamate receptor , chemistry , ampa receptor , receptor , biochemistry , genetics , fragile x , gene
Fragile X syndrome (FXS) is caused by the loss of functional fragile X mental retardation protein (FMRP). Loss of FMRP results in an elevated basal protein expression profile of FMRP targeted mRNA s, a loss of local metabotropic glutamate receptor (mGluR)‐regulated protein synthesis, exaggerated long‐term depression and corresponding learning and behavioral deficits. Evidence shows that blocking mG luR signaling in FXS models ameliorates these deficits. Therefore, understanding the signaling mechanisms downstream of mGluR stimulation may provide additional therapeutic targets for FXS. Kinase cascades are an integral mechanism regulating mGluR‐dependent protein translation. The c‐Jun N ‐terminal kinase (JNK) pathway has been shown to regulate mG luR‐dependent nuclear transcription; however, the involvement of JNK in local, synaptic signaling has not been explored. Here, we show that JNK is both necessary and sufficient for mG luR‐dependent expression of a subset of FMRP target proteins. In addition, JNK activity is basally elevated in fmr1 knockout mouse synapses, and blocking JNK activity reduces the over‐expression of post‐synaptic proteins in these mice. Together, these data suggest that JNK may be an important signaling mechanism downstream of mG luR stimulation, regulating FMRP‐dependent protein synthesis. Furthermore, local, post‐synaptic dysregulation of JNK activity may provide a viable target to ameliorate the deficits involved in FXS.Expression of many FMRP target proteins is enhanced in FXS. Here, we evaluated the role of JNKs in FXS. We found that JNK signaling is activated upon mGluR stimulation in wild‐type neurons. Conversely, JNK activity is basally elevated in fmr1 knockout. Inhibiting JNK reduced the expression of FMRP target proteins and driving JNK activity increased the expression of these proteins.