FK506-binding proteins (FKBPs) originally were described as ubiquitously expressed immunophillins that mediate the pharmacological activities of naturally occurring macrolide immunosuppressants such as FK506 and rapamycin. It is now known that FKBPs have a broader range of functions. FKBPs are peptidyl-prolyl cis-trans isomerases (PPiases) involved in the conversion of cis
-proline residues to a less sterically restricted trans
conformation. FKBPs also are involved in the regulation of intracellular calcium release, gene transcription, protein translation, and cellular trafficking (Harrar et al., 2001
). FKBP12, the smallest of member of the FKBP family, has a basic domain, a PPiase catalytic domain, and a drug-binding pocket, all of which are characteristic of the FKBP family.
FKBP12 modulates the activity of several receptor complexes, including ryanodine receptors (RyRs), transforming growth factor-β receptor complex, and inositol-P3
-receptors (Harrar et al., 2001
), but also influences protein kinase signaling. FKBP12 bound to rapamycin regulates the kinase, mammalian target of rapamycin (mTOR, also known as FRAP or RAFT) (Jacinto and Hall, 2003
). The regulation of mTOR and its downstream effectors are highly conserved from yeast to humans (Hay and Sonenberg, 2004
). The most studied function of mTOR is its role in regulating protein translation, primarily cap-dependent translation initiation. mTOR phosphorylates 4E-BP, an inhibitory protein that acts to sequester the translation initiation factor eIF4E (Klann and Dever, 2004
). Another important target of mTOR is p70 S6 kinase (S6K), which has been shown to phosphorylate and activate eIF4B, thereby stimulating the DEAD box helicase eIF4A to unwind the inhibitory secondary structure in the 5’ untranslated region of eukaryotic mRNAs (Raught et al., 2004
). Thus, activation of mTOR results in the stimulation of translation initiation via the regulation of both 4E-BP and S6K.
FKBP12 is the intracellular receptor for rapamycin, a commonly utilized inhibitor of mTOR signaling. Rapamycin-bound FKBP12 binds and inhibits mTOR (Brown et al., 1994
). mTOR also is regulated by other associated proteins (Kim et al., 2002
; Loewith et al., 2002
; Sarbassov et al., 2004
), including the regulatory associated protein of mTOR (Raptor); mTOR bound to Raptor is commonly referred to as mTOR complex 1 (mTORC1). Raptor enhances the interaction of mTOR with S6K, promoting cell growth. mTORC1 formation is inhibited by rapamycin, but the extent of the inhibition is dependent on the nutrient state of the cell, suggesting the existence of variable mTOR-Raptor interaction states (Kim et al., 2002
New protein synthesis is required for many long-lasting forms of synaptic plasticity and long-term memory (LTM) (Kelleher et al., 2004b
; Klann and Dever, 2004
). Given the central role of mTOR in translation control, ascertaining its regulation in neurons is vital to elucidating the regulation of protein synthesis during synaptic plasticity and memory. We examined the effects of the genetic deletion of the FKBP12 protein on mTOR signaling, synaptic plasticity and memory. In biochemical experiments we found that deletion of FKBP12 was associated with enhanced mTOR phosphorylation, an increase in the interaction between mTOR and Raptor, and enhanced phosphorylation of the mTOR target S6K. In electrophysiological studies we found that the deletion of FKBP12 resulted in enhanced late phase LTP (L-LTP) that was resistant to rapamycin, but was blocked by inhibitors of protein synthesis. Behavioral experiments revealed that the FKBP12 mutant mice exhibit enhanced contextual fear, repetitive behavior, and perseveration in several assays of memory, phenotypes that have been observed in several cognitive disorders, including autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), schizophrenia, and Huntington’s disease. Taken together, our findings demonstrate that FKBP12 normally acts to constrain the mTOR signaling during long-term synaptic plasticity, memory, and perseverative behaviors.