The neurotransmitter serotonin (5-HT) is widely diffused in the central nervous system and controls many brain functions, among which mood and cognition. Fragile X Syndrome is the most common form of inherited intellectual disability, frequently associated with epilepsy and autism. Fmr1 KO mice, an animal model of Fragile X Syndrome, display excessive metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD), altered dendritic spine morphology, learning deficit and autistic behavior. We have shown that activation of serotonin 5-HT7 receptors (5-HT7Rs) reverses mGluR-LTD in wild-type (wt) and Fmr1 KO mice. To identify the mechanisms underlying 5‑HT7R‑mediated effects, we used patch clamp on hippocampal slices from wt and Fmr1 KO mice to test the effects of 5-HT7R agonists on mGluR-LTD in the presence of specific blockers of intracellular messengers. Our results show that 5-HT7R activation reverses mGluR-LTD in wt and Fmr1 KO slices acting through a cAMP-dependent mechanism involving ERK, Cdk5 and GSK3 kinases and protein synthesis; we are currently investigating at which level these pathways interact. Consistent with our in vitro results on hippocampal slices, we found that in vivo systemic administration of a 5-HT7R agonist improved learning in wt mice and rescued dendritic spine morphology, learning and behavior in Fmr1 KO mice. Taken together, our data show that 5-HT7 receptors play a crucial role in learning and memory in physiological conditions and indicate that activation of 5-HT7 receptors might become a novel therapeutic strategy for Fragile X Syndrome. FINANCIAL SUPPORT: FRAXA Research Foundation (U.S.A.), grant 2013; Telethon Foundation (Italy), grant GGP13145.
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