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, 19 (3), 319-26

Protein Translation in Synaptic Plasticity: mGluR-LTD, Fragile X


Protein Translation in Synaptic Plasticity: mGluR-LTD, Fragile X

Maggie W Waung et al. Curr Opin Neurobiol.


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.


Figure 1
Figure 1. Acute blockade of Arc translation blocks mGluR-induced decreases in surface GluR1 and LTD of synaptic transmission
A1, Representative images of Arc immunofluorescence in dissociated hippocampal neurons. Antisense oligonucleotides directed against Arc mRNA, or mismatch oligonucleotides were introduced into 19–21 DIV neurons via a lipid-based delivery system. Neurons were treated with media (control) or DHPG and fixed 10 min after onset of treatment. A2, Quantification of the area of the dendritic Arc fluorescence reveal that either one of two unique Arc antisense oligonucleotides (Arc antisense and Arc antisense 2) block DHPG-induced increases in Arc protein without affecting basal Arc levels (in control mismatch oligo treated cultures). Data from 2 cultures per condition. B1, Representative images of surface GluR1 in neurons treated with antisense or mismatch oligonucleotides 30 min prior to media (control) or DHPG treatment. One hour after DHPG, neurons were fixed and processed for surface GluR1 immunofluorescence. B2, Quantified group data reveal that DHPG fails to induce long-term decreases in surface GluR1 in neurons pretreated with either Arc antisense oligonucleotides, in contrast to neurons treated with mismatch oligonucleotides. Data from 2–3 cultures/condition. In all images scale bars = 10 μm. C1 Inset: Schematic of recording configuration in a rat hippocampal slices. Antisense oligo was infused into the postsynaptic CA1 neuron. EPSCs were evoked by an extracellular stimulating electrode placed in the Schaffer collateral axons from CA3. Average normalized EPSC amplitudes of CA1 neurons from acute hippocampal slices recorded with pipettes containing 250 μM Arc antisense or mismatch oligonucleotide. DHPG (100 μM, 5 min) applied to the bath resulted in LTD of EPSC amplitudes in cells filled with mismatch oligonucleotide. In contrast, intracellular introduction of Arc antisense oligonucleotide via patch pipette blocks DHPG-induced LTD. N = 7 for each group. Above each plot are representative EPSCs from cells filled with Arc antisense oligonucleotide or mismatch oligonucleotide taken during pre-DHPG baseline (1) or 50 min after LTD induction (2; as indicated in group plot). Scale bars = 50 pA/10 msec.
Figure 2
Figure 2. Proposed mechanisms by which newly synthesis proteins mediate persistent decrease in surface AMPA receptors during mGluR-LTD
Brief activation of mGluR1/5 triggers rapid endocytosis of AMPARs that requires activity of the Tyr phosphatase STEP and basal levels of Arc. Tyr dephosphorylation of the GluR2 subunit of the AMPAR is correlated with mGluR-triggered AMPAR endocytosis, suggesting that this is the relevant phosphatase substrate. MGluRs also rapidly increase translation of Step, Map1b and Arc mRNA. MAP1B is required for mGluRs to induce long-term decreases in surface AMPARs perhaps by sequestering the AMPAR binding protein GRIP. New synthesis of Arc, and perhaps STEP, may maintain mGluR-LTD by causing persistent increases in AMPAR endocytosis rate.
Figure 3
Figure 3. Group 1 mGluRs stimulate translation through multiple pathways in neurons
mGluR5 regulates translation initiation through activation of the PI3K, mTOR and ERK pathways that converge on the initiation factor, eIF4E. mGluRs also stimulate p70S6K which is thought to generally enhance translation rate through phosphorylation of the S6 ribosomal subunit and translation of 5′TOP containing mRNAs encoding components of the translation apparatus, such as EF1a. mGluRs rapidly stimulate PP2A which results in a dephosphorylation of FMRP and translation of FMRP interacting mRNAs. mGluRs also inhibit elongation generally through activation of EF2K. The submaximal inhibition of general elongation is thought to make available initiation factors for translation of specific mRNAs, such as Arc and Map1b. Interestingly, mGluR5 complexes directly (EF2K and PP2A) or indirectly through Homer (EF2K and PIKE) with many signaling molecules that regulate translation. Interactions of mGluR5 with Homer are required for the ability of mGluRs to regulate translation initiation and perhaps elongation as well.

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