Multiple Gq-Coupled Receptors Converge on a Common Protein Synthesis-Dependent Long Term Depression That Is Affected in Fragile X Syndrome

Activation of Gq-coupled group I metabotropic glutamate receptors (mGluR1, mGluR5) induces long-term synaptic depression (LTD) that requires rapid, dendritic protein synthesis. The significance of protein synthesis-dependent mGluR LTD to cognitive function is highlighted by the recent finding that mGluR-dependent LTD is enhanced and protein synthesis-independent in the mouse model of fragile X syndrome mental retardation (FXS, Fmr1 KO mice). In fact, group I mGluR antagonism ameliorates some symptoms of FXS in model organisms. However, disagreement exists in the literature as to the specific roles of mGluR1 and mGluR5 in LTD. Using pharmacological and genetic manipulations, I find that mGluR1 or mGluR5 activation is sufficient to induce LTD. In contrast, I see a selective role for persistent mGluR1 activity in expression of LTD induced with the group I mGluR agonist, DHPG. These data demonstrate a novel role for mGluR1 in induction and expression of LTD at hippocampal Schaffer collateral-CA1 synapses and confirm a role for mGluR5 in induction of LTD at this synapse. LTD induced synaptically with paired-pulse low frequency stimulation (PP-LFS) is Gq- and protein synthesis-dependent and shares common signaling and expression mechanisms with DHPG-induced LTD. However, I find that PP-LFS LTD persists in the presence of group 1 mGluR antagonists and in mGluR1 or mGluR5 knockout mice. These data led to the hypothesis that Gq-coupled receptors other than mGluRs are activated by PP-LFS to induce LTD, and LTD mediated by these receptors should share similar signaling and expression mechanisms with mGluR LTD. A previous study shows that muscarinic acetylcholine receptors (mAChRs) activate protein synthesis in hippocampal CA1 dendrites. Data presented here demonstrate that PP-LFS activates both Gq-coupled mAChRs and mGluRs to induce LTD. Pharmacological activation of mAChRs induces LTD that requires rapid protein synthesis and activation of ERK and mTOR translational activation pathways. New proteins maintain mAChR-dependent LTD through a persistent decrease in surface AMPA receptors. In addition, mAChR LTD is enhanced and protein synthesis-independent in Fmr1 knock-out mice. These data reveal that multiple Gq-coupled receptors converge on a common protein synthesis-dependent LTD mechanism that is aberrant in FXS. These findings suggest novel therapeutic strategies for FXS in the form of mAChR antagonists.