FIGURE 1.

Amyloid-beta protein precursor and Aβ are key regulators of synaptic activity. APP is processed by α-, β-, and/or γ-secretases to produce soluble N-terminal domains of APP (sAPPα and sAPPβ), Aβ and C-terminal fragments. Aβ increases LTD, inhibits LTP (Koffie et al., 2011), induces calcium-dependent synaptic vesicle depletion at the presynaptic membrane (Parodi et al., 2010), binds to numerous postsynaptic surface proteins including NMDAR (Danysz and Parsons, 2012), activates mGluR₅ signaling (Casley et al., 2009; Renner et al., 2010), induces Arc and APP expression (Lacor et al., 2004; Westmark et al., 2011b) and interferes with normal NMDAR and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid receptor (AMPAR) trafficking by triggering receptor internalization (Hsieh et al., 2006; Ma and Klann, 2012). Group 1 mGluRs are anchored to NMDAR via a chain of scaffolding proteins including the long isoforms of Homer, Shank, and postsynaptic density protein 95 (PSD95). Aβ induces disassembly of Shank1 and Homer1b clusters (Roselli et al., 2009). Group 1 mGluRs are upstream of two pivotal signaling pathways, PI3 kinase/Akt/mTOR (mammalian target of rapamycin)/p70S6K and Ras/MAPK (mitogen-activated protein kinase)/p90S6K. Both of these pathways regulate the phosphorylation status of eIF4E, 4E-BPs, and ribosomal protein S6, which positively influence protein synthesis. Aβ and sAPP activate MAPK^ERK (Young et al., 2009; Chasseigneaux et al., 2011). Aβ both inhibits and activates mTOR signaling (Ma et al., 2010; Caccamo et al., 2011), and activates GSK3β (Takashima et al., 1996), a key regulator of numerous signaling pathways. APP, sAPP, and the intracellular C-terminal fragments also affect synaptic homeostasis. APP anchors cytoplasmic polyadenylation element binding factor (CPEB) to membranes and promotes polyadenylation-induced translation (Cao et al., 2005). sAPPα increases de novo protein synthesis (Claasen et al., 2009), enhances LTP (Taylor et al., 2008), shifts the frequency-dependency for induction of LTD (Ishida et al., 1997), and disrupts APP dimers at the plasma membrane (Gralle et al., 2009). While there is only a 17-amino acid difference between the differentially processed N-terminal fragments, sAPPα possesses synaptotrophic and neuroprotective activities while sAPPβ can be toxic (Zheng and Koo, 2011). The C-terminal fragment generated after amyloidogenic processing of APP is also neurotoxic and activates GSK3 (Ryan and Pimplikar, 2005). The 104 amino acid C-terminal fragment containing Aβ impairs LTP (Nalbantoglu et al., 1997). The levels of many synaptic proteins corresponding to a number of FMRP target mRNAs are constitutively elevated in the Fmr1^KO mouse. A few examples that are regulated by mGluR₅ are illustrated [ARC (activity-regulated cytoskeleton-associated protein), FMRP, PSD95, MAP1B (microtubule-associated protein 1B), striatal-enriched protein tyrosine phosphatase (STEP), and APP; Bassell and Warren, 2008; Goebel-Goody et al., 2012]. Overall, these data strongly suggest that APP and Aβ are among key LTD proteins whose over-expression during development play an important role in FXS pathogenesis. Key: major cellular processes (glutamate release, mGluR₅ signaling, AMPAR endocytosis, translation, LTD, LTP, and APP processing) are boxed. Receptors (mGluR₅, NMDAR, and GABA_BR) are inserted into the membrane and differentially colored. Scaffolding (Shank, Homer, Caveolin, and Pike), signaling molecules (MAPK, mToR, and GSK3), and translated proteins (ARC, FMRP, PSD95, and MAP1B) are oval-shaped and differentially colored. APP is colored fuchsia with the Aβ portion in light pink for amyloidogenic processing (β- and γ-secretase cleavage) and white for non-amyloidogenic processing (α-secretase cleavage). Secretases are denoted by the scissors symbols. Sharp arrowheads denote activation of a protein or process and rounded arrowheads denote inhibition of a protein or process.