5-HT7 receptors for serotonin (5-HT) are expressed in the hippocampus, a brain structure crucially involved in learning and memory, and modulate the intrinsic excitability of hippocampal neurons and glutamate-mediated synaptic transmission. We have recently shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type and in Fmr1 KO mice (Costa et al., Biol. Psych. 2012, 72:924-933), a mouse model of Fragile X syndrome (FXS) in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for FXS. In this perspective, we have studied novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on hippocampal synaptic plasticity using patch clamp on acute slices from wild-type and Fmr1 KO mice. We show that novel 5-HT7 ligands structurally related to LP-211, a potent, selective and brain-permeant 5-HT7 receptor agonist, behave as agonists at 5-HT7 receptors and are able to reverse mGluR-LTD in the synapse between CA3 and CA1 pyramidal neurons in the hippocampus from wild-type and Fmr1 KO mice. In addition, we have studied the biological effects of RA-7, a compound arising from in vivo metabolism of LP-211; the possible implications for systemic administration of LP-211 will be discussed. We are currently investigating the effects of LP-211 on typical abnormal features of Fmr1 KO mice, namely altered dendrite morphology, sensitivity to audiogenic seizures and learning impairment. Our results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and suggest that these molecules might become novel pharmacological tools for the therapy of Fragile X syndrome.
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