PAIP2A is expressed in the cell body and dendrites of pyramidal cells in the CA1 region of the mouse hippocampus (Figure 1A) and is present in the synaptosomal fraction prepared from adult hippocampus (Figure 1B). We investigated the role of PAIP2A in synaptic plasticity Inhibitor Library price and memory using Paip2a−/− mice ( Yanagiya et al., 2010). PAIP2A was not detected in the brain of Paip2a−/− mice, as determined by western blotting ( Figure S1A

available online). A statistically significant increase in the levels of PABP bound to mRNA in Paip2a−/− mice, as compared to wild-type (WT), was evident (29.3% ± 3.4%, p < 0.05; Figure 1C), consistent with the previously established inhibition of the PABP-poly(A) tail interaction by PAIP2A ( Khaleghpour et al., 2001). We did not detect any gross morphological abnormalities in the brain of Paip2a knockout (KO) mice as assessed by Nissl staining ( Figures S1B and S1C) or by immunohistochemistry of brain sections for synaptophysin, a marker of synapses ( Figure S1D). In addition, the number of VGLUT (presynaptic marker) and PSD-95 (postsynaptic

marker) puncta in stratum radiatum of CA1 hippocampus did not differ between WT and Paip2a−/− mice ( Figures S1E and S1F), and neither did spine density ( Figure S1G) or dendritic arbor ( Figure S2A). Since PAIP2A is a translational selleck kinase inhibitor repressor, we hypothesized that brain slices from Paip2a−/− mice should manifest enhanced protein synthesis-dependent LTP. A single high-frequency stimulation (1HFS) of the Schaffer collateral-CA1 synapses elicited transient short-lasting potentiation (E-LTP) of field excitatory postsynaptic potentials (fEPSPs) in slices from WT animals, which decays after 1.5 hr and does not require new protein synthesis ( Figure 1D). In striking contrast, in slices from Paip2a−/− littermates, 1HFS elicited

Metalloexopeptidase LTP that persisted for at least 3 hr after induction. The transition from transient to sustained potentiation after 1HFS in Paip2a−/− slices was protein synthesis dependent, as treatment with anisomycin, an inhibitor of protein synthesis, during tetanization abolished L-LTP in Paip2a−/− slices ( Figure 1E), similarly to the inhibition of theta-burst stimulation (TBS)-induced L-LTP in WT slices ( Figure S2B). Actinomycin-D, a transcription inhibitor, also reduced L-LTP in Paip2a−/− slices but to a lesser extent than anisomycin ( Figure 1E). It is important to note that basal synaptic transmission in Paip2a−/− slices was not different from that in WT slices as evidenced by the input-output relation of fEPSPs and paired-pulse facilitation ( Figures S2C and S2D, respectively), demonstrating that these effects are not due to changes in basal synaptic transmission. Next, we examined the effect of Paip2a ablation on L-LTP induced with TBS. Whereas in WT slices TBS induced persistent potentiation, in Paip2a−/− slices L-LTP was impaired ( Figure 1F).