Editors' ChoiceNeuroscience

Remembering Spatial Organization Requires Targeted Translation

Sci. Signal.  05 Aug 2014:
Vol. 7, Issue 337, pp. ec206
DOI: 10.1126/scisignal.2005760

Learning and memory formation depend on synaptic plasticity, the adjustment of synaptic strength in response to activity. Different types of learning rely on different directional adjustments. Spatial memory, learning the orientation of objects in one’s environment, relies on the long-term depression (LTD) of excitatory postsynaptic currents in the hippocampus that is triggered by activation of metabotropic glutamate receptors (mGluRs) in mice. Di Prisco et al. found that the synthesis of a specific protein by a process involving phosphorylation of the translation initiation factor eIF2α was required for mGluR-induced LTD and spatial learning in mice. The mGluR1 and mGluR5 (collectively mGluR1/5) agonist dihydroxyphenylglycine (DHPG) induced the phosphorylation of eIF2α and LTD in hippocampal slices from wild-type mice but not from heterozygous knock-in mice expressing a nonphosphorylatable eIF2α mutant. Activation of mGluR triggers the internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) from the cell surface. DHPG decreased the surface abundance of the AMPAR subunit GluR1 in cultured hippocampal neurons from control but not eIF2α-mutant mice. Increasing the phosphorylation of eIF2α by inducible expression and phosphorylation in transgenic mice or with an eIF2α phosphatase inhibitor (Sal003) in culture generated LTD in control but not eIF2α-mutant neurons. This eIF2α–mediated LTD response was insensitive to mGluR1/5 antagonists, indicating that activated eIF2α is a downstream mediator of mGluR-induced LTD. Polysomal RNA profiling and RNA sequencing showed that phosphorylation of eIF2α inhibited general protein synthesis while increasing the synthesis of select proteins, most abundant of which was oligophrenin-1 (OPHN1), a Rho guanosine triphosphatase that promotes endocytosis. In humans, mutations in OPHN1 are associated with cognitive disability. OPHN1 synthesis was not induced by DHPG in eIF2α-mutant neurons, and knocking down OPHN1 prevented DHPG- or Sal003-induced LTD. The abundance of phosphorylated eIF2α and, subsequently, OPHN1 was increased in the hippocampus when mice were exposed to new objects in their environment. Compared with control mice, eIF2α-mutant mice or mice injected in the hippocampus with a short hairpin RNA against OPHN1 spent more time exploring these same objects upon reexposure one day later. Thus, targeted protein synthesis by eIF2α mediates synaptic plasticity for spatial learning.

G. V. Di Prisco, W. Huang, S. A. Buffington, C.-C. Hsu, P. E. Bonnen, A. N. Placzek, C. Sidrauski, K. Krnjević, R. J. Kaufman, P. Walter, M. Costa-Mattioli, Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α. Nat. Neurosci. 17, 1073–1082 (2014). [PubMed]