All nuclear-transcribed

eukaryotic mRNAs contain at their 5′ end a m7GpppN structure (where m is a methyl group and N is any nucleotide) termed the “cap,” and most mRNAs contain a 3′-terminal poly(A) tail. Ribosome recruitment to the mRNA is facilitated by the eukaryotic initiation factor 4F (eIF4F), which binds the 5′ cap. eIF4F is a multisubunit complex composed of the following: (1) eIF4E, the cap-binding subunit; (2) eIF4G, a large scaffolding protein; and, (3) eIF4A, an RNA helicase. The assembly of the eIF4F complex is controlled by the mechanistic/mammalian target of rapamycin (mTOR) pathway, which, in neurons, is stimulated by activity and plays a key role in synaptic plasticity and memory formation (Hoeffer et al., 2008; Kelleher et al., 2004b). Translation is also enhanced by the poly(A) tail through the poly(A)-binding protein (PABP) (Derry et al., 2006). PABP binds simultaneously click here to the poly(A) tail and eIF4G, resulting in the mRNA circularization, which facilitates translation initiation (Gray et al., 2000; Kahvejian et al., 2001). Translation is Venetoclax ic50 also regulated by PABP-interacting proteins (PAIPs), which function to control PABP activity. PAIP1 stimulates translation via its interactions with PABP, eIF4A, and eIF3 (Martineau et al., 2008). Conversely, PAIP2 strongly inhibits translation by competing with the poly(A) tail and eIF4G for binding to PABP, thus reducing PABP-poly(A)

tail and PABP-eIF4G interactions (Karim et al., 2006; Khaleghpour et al., 2001). Two homologs of PAIP2 exist in mammals: PAIP2A and PAIP2B. No functional or mechanistic differences between PAIP2A and PAIP2B

have been reported; however, the tissue distributions of PAIP2A and PAIP2B differ at both the mRNA and protein levels in mice (Berlanga et al., 2006). until PAIP2A is expressed in the brain at much higher levels than PAIP2B (Yanagiya et al., 2010). Given the important role of PABP in translational control (Derry et al., 2006), its presence in dendrites (Muddashetty et al., 2002), and the pervasive paradigm of activating gene expression by removing inhibitory constraints (Abel et al., 1998; Shimizu et al., 2007), we reasoned that PAIP2A might play a role in controlling synaptic plasticity and memory. Here, we show that calcium-activated proteases, calpains, rapidly proteolyze PAIP2A in cultured neurons after stimulation with NMDA or with KCl-induced depolarization. Moreover, PAIP2A is rapidly degraded in hippocampal slices following tetanic stimulation and in the dorsal hippocampus after training for contextual memory. Hippocampal slices from Paip2a−/− mice exhibit a lowered threshold for induction of L-LTP, and Paip2a−/− mice exhibit enhanced spatial memory after weak training. The translation of CaMKIIα mRNA, which is essential for memory formation, is enhanced in Paip2a−/− mice, demonstrating that translation of this mRNA is constrained by PAIP2A.