De novo translation initiation in CA1 pyramidal cells is critical for hippocampal memory consolidation

Z. JIANG, J. BELFORTE, Y. LU, Y. YABE, J. PICKEL, C. SMITH, B. LU, K. NAKAZAWA

Washigton DC, USA

Congreso; Annual Meeting Society for Neuroscience; 2008

Society of Neuroscience

An essential role for new protein synthesis in synaptic plasticity and memory formation has been proposed based on previous studies using protein synthesis inhibitors (PSIs). However, PSIs are known to have significant side effects. It has been questioned whether memory impairments induced by PSIs are due to global protein synthesis inhibition or other cellular actions caused by PSIs. In addition, brain region or cell-type specific inhibition of protein synthesis by these drugs is hard to achieve. Therefore, the inducible genetic manipulation of translational machinery in particular brain regions and/or cell types has been desired. It is known that double-strand RNA-dependent protein kinase R (PKR) inhibits protein synthesis by phosphorylating eIF2á, a key factor in translation initiation. Previous studies indicated that dimerization of the PKR kinase domain is necessary and sufficient for its kinase activity. To establish an inducible genetic manipulation of the protein translation system, we fused FKBP12, a chemically induced dimerization cassette, to the PKR kinase domain to generate floxed-PKR transgenic strains. After crossing one floxed-PKR line, fPKR#6, with a forebrain specific Cre line, T29-1, expression of PKR was targeted to the hippocampus, primarily CA1 and DG excitatory neurons. Activation of PKR with AP20187 infusion induced a selective increase of phospho-eIF2á and ATF4 in CA1 pyramidal cells. L-LTP, but not E-LTP, at CA1 synapses was impaired in hippocampal slices following activation of PKR. Mutant mice with the drug infusion were impaired in habituation to a new open field, context discrimination in a step-through avoidance task, and formation of contextual, but not auditory, fear memory 24 hr after the trainings. However, retrieval of contextual fear memory 30 min after the training was not affected by the manipulation. These results suggest that manipulation of protein synthesis in CA1 pyramidal cells is able to impair hippocampal-dependent memory consolidation. Despite these behavioral deficits, overall levels of protein synthesis in CA1 were not changed after PKR activation. In contrast, significant decreases in protein synthesis mediated by anisomycin were not sufficient to induce memory impairments. This double dissociation suggests that global de novo protein synthesis inhibition per se does not contribute to impairments in memory consolidation. It rather suggests a critical role of particular protein pathways in CA1, such as ATF4 and its downstream targets, in the consolidation of hippocampal-dependent memories.