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. 2016 Jun 30;10:136. doi: 10.3389/fnbeh.2016.00136

Figure 1.

Figure 1

Targeting the cAMP signaling cascade increases social interaction. (A) The cAMP signaling cascade. The three treatments used in this study increase cAMP signaling in the fly and mouse. It has been demonstrated that antagonizing or dampening the signaling of either of the mGluR pathways can rescue multiple phenotypes in the fly and mouse models of Fragile X including memory, audiogenic seizure and enhanced mGluR-LTD (McBride et al., 2005; Yan et al., 2005; Dolen et al., 2007; Choi et al., 2010, 2011). Additionally, lithium has demonstrated efficacy in rescuing cognitive abilities, audiogenic seizure and enhanced mGluR-LTD in fly and mouse models as well as in human patients (McBride et al., 2005; Berry-Kravis et al., 2008; Min et al., 2009b; Choi et al., 2010, 2011; Yuskaitis et al., 2010; Liu et al., 2011). As is displayed in the figure, PDE-4 also intersects in this signaling cascade. The common aspect is that lithium, mGluR antagonists and PDE-4 inhibitors should all result in increasing cAMP signaling and increased PKA activity. Each should inhibit GSK-3B activity, which may be read out as phosphorylation of tau. Tau phosphorylation has been demonstrated to phosphorylate and activate mTOR, although many pathways feed into mTOR signaling. (B–D) Social interaction (Naive courtship of sham trained males) was examined after drug or vehicle treatment. (B–D) Naive courtship of WT and FS flies exposed to drug or drug vehicle control containing food. Mean CIs (±SEM) are plotted; Ns are indicated above each bar for all groups. The comparisons shown on the graphs are between vehicle and drug treatment with the same genotype and between WT and FS treatment for the vehicle treatment. For levels of significance, **p < 0.01; ***p < 0.001. Filled bars indicate WT males; open bars indicate FS males. (B) Flies were raised on regular food and starting on the 1st day of adulthood placed on either vehicle control food containing 5 mM NaCl vehicle or food supplemented with 5 mM lithium. With vehicle treatment, FS males court virgin females less vigorously than do WT flies (p < 0.001) represented by asterisks over the FS vehicle bar. FS flies treated with lithium spend a higher percentage of time engaged in courtship compared to vehicle treated FS flies, asterisks above the FS lithium bar. WT flies treated with lithium demonstrated decreased courtship compared to vehicle treated WT flies, asterisks over the WT lithium bar. (C) Flies were raised on regular food and starting on the 1st day of adulthood placed on either vehicle control food containing DMSO vehicle or food supplemented with either 400 nM LY341495 or 8.6 μM MPEP. With vehicle treatment, FS males court virgin females less vigorously than do WT flies, asterisks over the FS vehicle bar. FS flies treated with either MPEP or LY341495 spent a higher percentage of time engaged in courtship compared to vehicle treated FS flies, asterisks over the FS LY341495 and FS MPEP bars. WT flies treated with either MPEP or LY341495 demonstrated decreased courtship compared to vehicle treated flies, asterisks over the WT MPEP and WT LY341495 bars. (D) Flies were raised on regular food and starting on the 1st day of adulthood placed on either vehicle control food containing DMSO vehicle or food supplemented with either 50 μM Rolipram (Roli) or 20 μM Ro-20-1724 (Ro-20). With vehicle treatment, FS males court virgin females less vigorously than do WT flies, asterisks over the FS vehicle bar. FS flies treated with either rolipram or Ro-20-1724 spent a higher percentage of time engaged in courtship compared to vehicle treated FS flies, asterisks above the FS rolipram and FS Ro-20-1724 bars. WT flies treated with either rolipram or Ro-20-1724 demonstrated no change in the time spent engaged in courtship compared to vehicle treated flies.