Journal
JOURNAL OF NEUROSCIENCE
Volume 27, Issue 43, Pages 11624-11634Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2266-07.2007
Keywords
muscarinic acetylcholine; Gq coupled; metabotropic glutamate; hippocampus; Fragile X syndrome; long-term depression; protein synthesis
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Funding
- NINDS NIH HHS [1F31NS050992, NS045711] Funding Source: Medline
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Gq-coupled, M-1 muscarinic acetylcholine receptors (mAChRs) facilitate hippocampal learning, memory, and synaptic plasticity. M1 mAChRs induce long-term synaptic depression (LTD), but little is known about the underlying mechanisms of mAChR-dependent LTD and its link to cognitive function. Here, we demonstrate that chemical activation of M-1 mAChRs induces LTD in hippocampal area CA1, which relies on rapid protein synthesis, as well as the extracellular signal-regulated kinase and mammalian target of rapamycin translational activation pathways. Synaptic stimulation of M1 mAChRs, alone, or together with the Gq-coupled glutamate receptors (mGluRs), also results in protein synthesis-dependent LTD. New proteins maintain mAChR-dependent LTD through a persistent decrease in surface AMPA receptors. mAChRs stimulate translation of the RNA-binding protein, Fragile X mental retardation protein ( FMRP) and FMRP target mRNAs. In mice without FMRP (Fmr1knock-out), a model for human Fragile X syndrome mental retardation (FXS), both mGluR and mAChR-dependent protein synthesis and LTD are affected. Our results reveal that multiple Gq-coupled receptors converge on a common protein synthesis-dependent LTD mechanism, which is aberrant in FXS. These findings suggest novel therapeutic strategies for FXS in the form of mAChR antagonists.
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