Activation of 5-HT7 receptors for serotonin rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome through a cyclic AMP-mediated mechanism involving Cyclin-dependent Kinase 5 and protein synthesis
| Autor: | L. CIRANNA1, L. COSTA2, L. M. SARDONE1, M. SPATUZZA3, C. M. BONACCORSO4, S. D'ANTONI3, M. LEOPOLDO5, E. LACIVITA5, M. V. CATANIA3, 4 |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | 46 th Annual Meeting of Neuroscience, San Diego, 12-16/11/2016 info:cnr-pdr/source/autori:L. CIRANNA1, L. COSTA2, L. M. SARDONE1, M. SPATUZZA3, C. M. BONACCORSO4, S. D'ANTONI3, M. LEOPOLDO5, E. LACIVITA5, M. V. CATANIA3,4/congresso_nome:46 th Annual Meeting of Neuroscience/congresso_luogo:San Diego/congresso_data:12-16%2F11%2F2016/anno:2016/pagina_da:/pagina_a:/intervallo_pagine |
| Popis: | Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability, frequently associated with epilepsy and autism. Fmr1 KO mice, a model of FXS, display excessive metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD), altered dendritic spine morphology, learning deficit and autistic behavior. We have shown that 5-HT7 receptor (5-HT7R) agonists reverse mGluR-LTD in wt and Fmr1 KO mice (Costa et al., Biol. Psych. 2012, 72:924-933). We have preliminary data showing that 5-HT7R agonists also rescue dendritic spine morphology, learning and behavior in Fmr1KO mice, suggesting that they might become a novel therapeutic strategy for FXS. To identify the mechanisms underlying 5-HT7R-mediated effects, we used patch clamp on hippocampal slices from wild-type (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. LP-211, a selective 5-HT7 R agonist, reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1 KO slices. The effect of LP-211 was mimicked by forskolin and was abolished by the adenylate cyclase inhibitor SQ22536. The effect of LP-211 persisted in the presence of cAMPS-Rp or PKA inhibitor peptide fragment 6-22 (PKA inhibitors) or PD98059 (a MEK/ERK inhibitor), but was reduced in the presence of lithium (a PI3K/GSK3 inhibitor) and was completely abolished in the presence of SB216763 (a GSK3 inhibitor), roscovitine (a Cdk5 inhibitor) or anisomycin (a protein translation inhibitor). Taken together our data show that 5-HT7 receptor activation reverses mGluR-LTD acting through a cAMP-dependent mechanism involving Cdk5 and GSK3 kinases and protein synthesis; we are currently investigating at which level these pathways interact. |
| Databáze: | OpenAIRE |
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