Figure 1.
Convergence and divergence of mechanisms for protein synthesis-dependent LTP and LTD. Protein synthesis-dependent LTP (L-LTP) and mGluR-LTD activate and use similar, if not identical, pathways. To simplify, not all protein synthesis regulatory pathways are included, and second-messenger pathways upstream of ERK and PI3 kinase (PI3K) are omitted. Coactivation of NMDARs and dopamine D1/D5 receptors initiates the insertion of glutamate receptors to the synaptic surface and stimulates both ERK and PI3 kinase. Alternatively, agonists of mGluR1/5 receptors initiate the internalization of glutamate receptors but similarly activate the ERK and PI3 kinase pathways. L-LTP- and mGluR-LTD-inducing stimuli phosphorylate ERK, Mnk1, and eIF4E and stimulate eIF4F initiation complex assembly. Activated PI3 kinase phosphorylates mTOR, which in turn phosphorylates and inactivates the negative regulator of cap-dependent translation initiation, 4EBP, thereby enhancing translation initiation. Activated mTOR additionally phosphorylates and activates S6K (ribosomal S6 kinase), which leads to increased TOP (5′ terminal oligopyrimidine tract)-dependent translation. Proteins translated in response to synaptic activity may facilitate or maintain alterations in surface receptor number, synapse size, and/or synapse number. A few selected proteins, the synthesis of which have been demonstrated or are required for protein synthesis-dependent plasticity by the two different stimulation paradigms, are listed.