Hypersensitivity to mGluR5 and ERK1/2 Leads to Excessive Protein Synthesis in the Hippocampus of a Mouse Model of Fragile X Syndrome

Journal of Neuroscience - Tập 30 Số 46 - Trang 15616-15627 - 2010
Emily K. Osterweil1, Dilja Krueger‐Burg2,3, Kimberly Reinhold2,3, Mark F. Bear2,3
1Department of Brain and Cognitive Sciences, Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
2Department of Brain and Cognitive Sciences, Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
3The Picower Institute for Learning and Memory, MIT 46-3301, 43 Vassar Street, Cambridge, MA 02139.

Tóm tắt

Fragile X syndrome (FXS) is caused by loss of theFMR1gene product FMRP (fragile X mental retardation protein), a repressor of mRNA translation. According to the metabotropic glutamate receptor (mGluR) theory of FXS, excessive protein synthesis downstream of mGluR5 activation causes the synaptic pathophysiology that underlies multiple aspects of FXS. Here, we use anin vitroassay of protein synthesis in the hippocampus of maleFmr1knock-out (KO) mice to explore the molecular mechanisms involved in this core biochemical phenotype under conditions where aberrant synaptic physiology has been observed. We find that elevated basal protein synthesis inFmr1KO mice is selectively reduced to wild-type levels by acute inhibition of mGluR5 or ERK1/2, but not by inhibition of mTOR (mammalian target of rapamycin). The mGluR5-ERK1/2 pathway is not constitutively overactive in theFmr1KO, however, suggesting that mRNA translation is hypersensitive to basal ERK1/2 activation in the absence of FMRP. We find that hypersensitivity to ERK1/2 pathway activation also contributes to audiogenic seizure susceptibility in theFmr1KO. These results suggest that the ERK1/2 pathway, and other neurotransmitter systems that stimulate protein synthesis via ERK1/2, represent additional therapeutic targets for FXS.

Từ khóa


Tài liệu tham khảo

10.1016/j.pain.2004.06.009

10.1128/MCB.00201-08

10.1073/pnas.0409803102

10.1126/science.7692601

10.1152/jn.00449.2010

10.1007/978-3-642-56688-2_5

10.1523/JNEUROSCI.5196-05.2006

10.1016/j.tins.2004.04.009

10.1124/mol.63.1.128

10.1017/S0012162201002833

10.1038/nn.2175

10.1016/S0092-8674(01)00568-2

10.1002/neu.480251106

10.1016/j.neuropharm.2006.07.003

10.1016/S0304-3940(01)02258-3

10.1091/mbc.5.5.549

10.1016/j.nbd.2008.04.002

10.1113/jphysiol.2008.150722

10.1016/j.neuron.2007.12.001

10.1038/nm1788

10.1046/j.1460-9568.1999.00626.x

10.1016/j.mcn.2006.11.015

10.1523/JNEUROSCI.5407-03.2004

10.1002/jcb.21633

10.1146/annurev.biochem.68.1.913

10.1074/jbc.273.23.14484

10.1111/j.1471-4159.2004.02815.x

10.1523/JNEUROSCI.0995-04.2004

10.1016/j.neuron.2006.07.005

10.1126/science.288.5469.1254

Huber, 2001, Chemical induction of mGluR5- and protein synthesis–dependent long-term depression in hippocampal area CA1, J Neurophysiol, 86, 321, 10.1152/jn.2001.86.1.321

10.1073/pnas.122205699

10.1016/0896-6273(92)90066-M

10.1073/pnas.231485698

10.1101/lm.3.2-3.188

10.1111/j.1471-4159.2006.04158.x

Karachot, 2001, Induction of long-term depression in cerebellar Purkinje cells requires a rapidly turned over protein, J Neurophysiol, 86, 280, 10.1152/jn.2001.86.1.280

10.1016/S0092-8674(04)00115-1

10.1073/pnas.0800257105

Kirov, 1999, Slices have more synapses than perfusion-fixed hippocampus from both young and mature rats, J Neurosci, 19, 2876, 10.1523/JNEUROSCI.19-08-02876.1999

10.1111/j.1460-9568.2007.05901.x

10.1523/JNEUROSCI.2910-08.2009

10.1093/hmg/10.4.329

10.1523/JNEUROSCI.2624-07.2007

10.1093/nar/29.11.2276

10.1006/meth.1999.0766

10.1523/JNEUROSCI.4360-04.2005

10.1093/hmg/11.24.3007

10.1523/JNEUROSCI.0955-08.2008

Merlin, 1998, Requirement of protein synthesis for group I mGluR-mediated induction of epileptiform discharges, J Neurophysiol, 80, 989, 10.1152/jn.1998.80.2.989

10.1523/JNEUROSCI.0937-07.2007

10.1073/pnas.0707484104

10.1038/nn.2477

10.1152/jn.01316.2005

10.1083/jcb.200410091

10.1016/j.neuron.2008.05.023

10.1042/BJ20070024

10.1523/JNEUROSCI.1118-06.2006

10.1523/JNEUROSCI.0093-05.2005

10.1093/cercor/bhn163

Raymond, 2000, Metabotropic glutamate receptors trigger homosynaptic protein synthesis to prolong long-term potentiation, J Neurosci, 20, 969, 10.1523/JNEUROSCI.20-03-00969.2000

10.1016/j.tibs.2007.04.004

10.1523/JNEUROSCI.5019-07.2008

10.1016/j.conb.2005.08.009

10.1523/JNEUROSCI.1739-04.2004

10.1523/JNEUROSCI.3696-09.2010

10.1523/JNEUROSCI.2457-04.2004

10.1016/S0092-8674(00)81780-8

10.1073/pnas.2336265100

10.1093/hmg/ddl422

10.1111/j.1601-183X.2005.00134.x

10.1016/0092-8674(91)90397-H

10.1128/MCB.25.7.2558-2572.2005

10.1073/pnas.90.15.7168

10.1073/pnas.94.10.5395

10.1073/pnas.0407533101

10.1111/j.1471-4159.1984.tb12788.x

10.1016/j.neuropharm.2005.06.004

10.1016/S0092-8674(03)00079-5

10.1523/JNEUROSCI.3893-08.2009

Thông tin
Thông tin xuất bản

Journal of Neuroscience

Tập 30 Số 46

15616-15627

Thông tin tác giả