Metabotropic Glutamate Receptors Trigger Homosynaptic Protein Synthesis to Prolong Long-Term Potentiation

Abstract

We investigated the mechanisms by which previous "priming" activation of group I metabotropic glutamate receptors (mGluRs) facilitates the persistence of long-term potentiation (LTP) in area CA1 of rat hippocampal slices. Priming of LTP was elicited by either pharmacological or synaptic activation of mGluRs before a weak tetanic stimulus that normally produced only a rapidly decaying phase of LTP that did not involve protein synthesis or mGluRs. Pharmacological priming of LTP persistence by a selective group I mGluR agonist was blocked by an inhibitor of group I mGluRs and by inhibitors of translation, but not by a transcriptional inhibitor. The same mGluR agonist increased (35)S-methionine incorporation into slice proteins. LTP could also be facilitated using a synaptic stimulation priming protocol, and this effect was similarly blocked by group I mGluR and protein synthesis inhibitors. Furthermore, using a two-pathway protocol, the synaptic priming of LTP was found to be input-specific. To test for the contribution of group I mGluRs and protein synthesis to LTP in nonprimed slices, a longer duration control tetanization protocol was used to elicit a more slowly decaying form of LTP than did the weak tetanus used in the previous experiments. The persistence of the LTP induced by this stronger tetanus was dependent on mGluR activation and protein synthesis but not on transcription. Together, these results suggest that mGluRs couple to nearby protein synthesis machinery to homosynaptically regulate an intermediate phase of LTP dependent on new proteins made from pre-existing mRNA.

Protein synthesis in the dendrite

“…Interestingly, the newly synthesized proteins promote LTP stability in an input-specific manner. The homosynaptic restriction of the function of newly synthesized proteins is consistent with the idea that at least some of the new proteins that are essential for LTP expression are synthesized at the activated synapses (Raymond et al 2000). Huber et al (2000) recently reported that LTD induced by mGluR stimulation, in CA1 stratum radiatum severed from cell body layers, could be blocked by translational inhibitors, indicating a requirement for local protein synthesis for the expression of this form of LTD.…”

“…However, inhibition of protein synthesis diminished only the increase in MAP2, not αCaMKII protein in the dendritic domains (Steward & Halpain 1999), indicating a protein-synthesis-independent mechanism for the observed increase in αCaMKII protein in the activated dendrites. Signals that are mediated by NMDA mGluRs are probably involved in triggering regulated local protein synthesis after synaptic activation (Raymond et al 2000;Scheetz et al 2000). Protein synthesis regulated by synaptic activity has been reported in the sensory neuron processes of Aplysia, and local application of protein synthesis inhibitors at a particular synapse can block long-term facilitation (LTF) at this synapse, but not at the other synapses on the same cells (Martin et al 1997).…”

“…These results indicate that there might be protein synthesis events that occur in the transected dendrites that are essential for the expression of BDNF-induced plasticity. Recently, Raymond et al (2000) reported that activation of metabotropic glutamate receptors contributes to LTP expression by triggering new protein synthesis. Interestingly, the newly synthesized proteins promote LTP stability in an input-specific manner.…”

The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95

“…Application of DHPG onto either hippocampal or cerebellar slices induces a long-term depression that requires dendritic protein synthesis but not transcription (35,40,41). Furthermore, DHPG application has also been reported to enhance both hippocampal long-term potentiation and the epileptogenic effects of picrotoxin in a protein synthesisdependent fashion (42,43). The requirements for protein synthesis in these various paradigms are very brief (10-15 min), suggesting that a ''pulse'' of translation is rapidly activated and then turned off (42,44).…”

Fragile X: Translation in Action

“…A case in point is a form of LTD triggered by mGluR5 activation in the hippocampus, which requires mRNA translation but not transcription (Huber et al, 2000). The same can be said of mGluR-dependent epileptogenesis (Merlin et al, 1998), dendritic spine elongation (Vanderklish and Edelman, 2002), LTP priming (Raymond et al, 2000), and LTP reversal (Zho et al, 2002) in the hippocampus.…”