Figure 4: Memory Suppressors of Consolidation.

Memory suppressor genes are in bold and color-coded green (fly), blue (mouse), and purple (both mouse and fly). A) PDEs regulate cAMP levels by converting cAMP to 5’-AMP. Activation of PKA by cAMP promotes consolidation through the phosphorylation of CREB but also inhibits consolidated ARM in Drosophila through an unknown mechanism. In Drosophila, ROCK activity enhances ARM and inhibits PSD-LTM. ROCK activity is suppressed by ERK-independent Ras signaling. Phosphorylated CREB binds CRE and drives transcription of mRNA required for memory formation. Proteins that inhibit CREB-dependent transcription, like ATF4 and ICER, suppress consolidation. Following transcription, memory-relevant mRNA can be reduced by small, non-coding RNAs (miRNA, piRNA) that either prevent translation or promote mRNA degradation. Dicer is required for the processing of pre-miRNA and piwil is required for piRNA-mediated mRNA degradation.

B) Regulation of translation factors by inhibitory proteins through phosphorylation or protein-protein interactions prevents ribosomal translation of mRNA to protein. Phosphorylation of the alpha subunit of eIF2 by PKR, GCN2, and PERK promotes translation of ATF4 and suppresses the synthesis of memory-promoting proteins. Fear conditioning stimulates dephosphorylation of eIF2α thereby facilitating consolidation. Fear conditioning also promotes consolidation by disinhibiting mTOR and PABP. FKBP12 association with mTOR prevents mTOR/raptor complex formation and subsequent control of translation regulators by mTOR/raptor. PAIP2A complex formation with PABP prevents PABP association with mRNA poly(A) tails. Fear conditioning drives the degradation of PAIP2A, freeing PABP to facilitate translation through its direct interaction with mRNA.