Protein translation in synaptic plasticity: mGluR-LTD, Fragile X

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Synaptically activated, rapid and dendritic synthesis of new proteins has long been proposed to mediate long-lasting changes at the synapse [Steward O, Schuman EM: Protein synthesis at synaptic sites on dendrites.Annu Rev Neurosci 2001, 24:299-325]. Studies of group 1 metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) have provided new insight into dendritic or local translation and plasticity. Here we highlight these exciting results and discuss how synaptic activity controls local translation, the proteins that are synthesized in dendrites, how they affect synaptic function and how altered local translational control contributes to a form of human mental retardation, Fragile X Syndrome.

Section snippets

Rapid postsynaptic translation is required for mGluR-dependent LTD

Principal neurons possess on average 10 000 excitatory synapses. Plasticity of individual or localized regions of synapses is necessary for the information storage capacity of the brain. Upon the discovery of polyribosomes within dendritic shafts and spines, it was suggested that rapid dendritic protein synthesis, triggered by synaptic activity, may serve as a mechanism for long-term plasticity at specific synapses [1]. Empirical data support the role of dendritic protein synthesis in the

mGluR-LTD is altered in the Fragile X Syndrome mouse model

Understanding the mechanisms and function of mGluR-LTD has relevance for human neurological disease because mGluR-LTD is altered in a mouse model of mental retardation and autism, Fragile X Syndrome (FXS). Fragile X Syndrome results from loss of function mutations in Fmr1, which encodes an RNA binding protein, Fragile X mental retardation protein (FMRP) [9]. FMRP associates with dendritic mRNAs and RNA granules, as well as translating polyribosomes, while Fmr1 mRNA is itself present in

Expression mechanisms of mGluR-LTD and candidate ‘LTD proteins’

Determining the molecular mechanisms of mGluR-LTD is essential to understanding how newly synthesized proteins in dendrites mediate plasticity as well as how and why plasticity is altered in Fragile X Syndrome. Activation of mGluRs causes a long-term decrease in surface AMPARs, both GluR1 and GluR2 subunits, lasting for at least an hour [20, 21]. AMPAR endocytosis is required for mGluR-LTD given that postsynaptic injection of D15, a peptide which interferes with dynamin–amphiphysin interactions

Protein synthesis dependent mGluR-LTD in other brain regions

Gq coupled receptor and protein synthesis dependent LTD is observed in multiple brain regions including the neocortex, cerebellum, ventral tegmental area (VTA) and dentate gyrus [8, 30, 31, 32••, 33]. MGluR-LTD has been most well characterized at the cerebellar granule cell-Purkinje cell synapse where strong evidence links LTD to cerebellar dependent learning. Like hippocampal mGluR-LTD, cerebellar mGluR-LTD is mediated by decreases in surface AMPARs and requires new protein synthesis,

mGluR activation of translation initiation

Studies of mGluR-LTD have provided critical knowledge of how synaptic activity activates rapid protein synthesis. Evidence supports the view that mGluRs regulate translation at multiple levels, through regulation of general translation factors as well as RNA binding proteins such as FMRP (Figure 3). MGluR activity stimulates translation initiation through 2 major signaling pathways, the ERK-MAPK and PI3K-mTOR pathways (Figure 3). To initiate translation, mGluRs trigger phosphorylation of

Concluding remarks

The study of mGluR-dependent LTD has provided mechanistic insight into how synaptic activity rapidly activates translation in neurons and in turn, how newly synthesized proteins alter synaptic function. This basic knowledge, in turn guided fruitful experiments into the neuronal function of the mental retardation linked gene Fmr1, the neurobiological deficits in FXS, and the development of novel therapies for the disease [49]. Important questions remain, such as: how are the various

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This research was supported by the grants from the National Institutes of Health NS045711, HD052731, Autism Speaks (KMH), and the UTSW Medical Scientist Training Program T32 GM08014 (MWW).

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