Effects of 5-HT7 receptor activation on dendritic spines and mGluR-LTD in Wild Type and Fmr1 knockout mice.

We have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild type (WT) and in Fmr1 knockout (KO) mice (Costa et al., 2012), a mouse model of Fragile X syndrome (FXS) characterized by an abnormally enhanced mGluR-LTD. Aim. Here, we assessed whether the activation of 5-HT7 receptor affected dendritic spine morphology, a typical abnormal feature of Fmr1 KO mice. We also investigated the intracellular cascades underlying the effect of 5-HT7 activation on mGluR-LTD. Methods. DiI labelling and confocal imaging were used to evaluate dendritic spine morphology in brain slices of mice systemically treated with the compound LP-211, a potent, selective and brain-permeant 5-HT7 receptor agonist (Hedlund et al., 2010). Western blotting analysis was used to study the distribution of 5-HT7 receptor in synaptic compartments and its signaling cascades in the cortex and hippocampus of WT and Fmr1 KO mice. mGluR-LTD was studied by patch-clamp technique. Results. 5-HT7 receptor was detected in the post- and pre-synaptic fraction of synaptosomes from both WT and Fmr1 KO mice. LP-211 treatment caused a decrease in the total density of spines in Fmr1 KO mice, with a major effect on thin spines. LP-211 induced ERK activation in acute slice preparation. Inhibition of adenylate cyclase reversed the effect of LP-211 on mGluR-LTD in both WT and Fmr1 KO mice. Conclusions. Our data support the view that the activation of 5-HT7 receptor might be a new pharmacological strategy in the therapy of FXS. Support: Telethon Foundation, grant GGP13145, IRCCS Oasi Maria Santissima, Troina (EN), Italy