[Abstract Title]. - Society for Neuroscience

Topic: F.02.h. Memory modulation, consolidation, and reconsolidation
Support: NIMH IRP
Title: De novo translation initiation in CA1 pyramidal cells is critical for hippocampal memory
consolidation
Authors: *Z. JIANG, J. BELFORTE, Y. LU, Y. YABE, J. PICKEL, C. SMITH, B. LU, K.
NAKAZAWA;
NIMH, Bethesda, MD
Abstract: 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 eIF2α, 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-eIF2α 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.
Disclosures: Z. Jiang, None; J. Belforte, None; Y. Lu, None; Y. Yabe, None; J. Pickel,
None; C. Smith, None; B. Lu, None; K. Nakazawa, None.