In support of our model, we showed that in the contextual fear conditioning task strong training of Paip2a+/− mice, in which the PAIP2A level is reduced by half, resulted in enhancement of LTM, conceivably because the activity-induced translation is enhanced to a lower extent that does not lead to L-LTP and memory deficits. In summary, we have uncovered a mechanism for activity-dependent regulation of mRNA translation in the mammalian brain through the control of PABP activity by the PABP-binding protein PAIP2A. We show that degradation of PAIP2A by calpains
releases PABP from inhibitory PAIP2-PABP complexes thereby enhancing PABP binding to memory-related mRNAs and stimulating their translation. Thus, PAIP2A is a negative
translational regulator of mammalian FG-4592 datasheet synaptic plasticity and memory. Paip2a−/− and Paip2b−/− mice ( Yanagiya et al., 2010) were backcrossed for more than 10 generations to C57BL/6J mice. For all behavioral tasks, 8- to 12-week-old Paip2a−/− and Paip2b−/− and their male WT littermates were used. The experimenter was blind to the genotype in all studies. Food and water were provided ad libitum, and mice were kept on a 12:12 hr light/dark cycle (lights on at 08:00 hr). All procedures complied with Canadian Council on Animal Care guidelines and were approved by Université de Montréal’s and McGill University’s animal care committees. Transverse Epacadostat order hippocampal slices (400 μm), prepared from WT or Paip2a−/− male littermates (6–8 weeks old), were allowed to recover submerged for at least 2 hr at 32°C in oxygenated artificial
cerebrospinal fluid (ACSF) containing 124 mM NaCl, 2.5 mM KCl, 1.25 mM NaH2PO4, 1.3 mM MgSO4, 2.5 mM MYO10 CaCl2, 26 mM NaHCO3 and 10 mM glucose, and for an additional 30 min submerged in a recording chamber at 27°C–28°C while continuously perfused with ACSF. fEPSPs were recorded in CA1 stratum radiatum with glass electrodes (2–3 MΩ) filled with ASCF. Schaffer collateral fEPSPs were evoked by stimulation with a concentric bipolar tungsten stimulating electrode placed in midstratum radiatum proximal to CA3 region. For two-pathway experiments, two stimulating electrodes were placed in the proximal and distal CA1 stratum radiatum on either side of the recording electrode. The independence between pathways was verified at the onset of every experiment. Baseline stimulation was applied at 0.033 Hz by delivering 0.1 ms pulses, with intensity adjusted to evoke 35% of maximal fEPSPs. To induce LTP with tetanic stimulation, a single train was delivered at 100 Hz for 1 s. TBS consisted of 15 bursts of four pulses at 100 Hz separated by 200 ms intervals. DHPG (50 μM, Tocris) was added to ACSF for 10 min to induce mGluR-mediated LTD. To induce NMDA-receptor-mediated LTD with LFS, 900 pulses at 1 Hz were delivered. Slices used for LFS-induced LTD were allowed to recover for at least 4 hr before the experiment.