Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

Abstract

Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, 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 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compound BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compounds RA-7 and PM-20, respectively arising from in vivo metabolism of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacological tools for the therapy of Fragile X Syndrome.

In the search for a lead structure among series of potent and selective hydantoin 5‐HT7R agents: The drug‐likeness in vitro study

“…This study is focused on the search of a lead compound by "drug-likeness" estimation of the first series of selective and potent 5-HT 7 R ligands among 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-aryl-piperazin-1yl)propyl)-5-methylimidazolidine-2,4-dione derivatives (11)(12)(13)(14)(15)(16). One out of the main reasons disqualifying the 5-HT 7 R ligands is weak drugability properties, including metabolic instability or low permeability.…”

Involvement of Brain 5-HT7 Receptors in the Formation of Stress Adaptation in Mice

“…Activation of 5-HT 7 receptors by agonists was shown to reverse metabotropic glutamate receptor-mediated long-term depression and to correct a synaptic malfunction in Fmr1 knock-out mice, which is a mouse model of Fragile X Syndrome, the most common form of inherited intellectual disability associated with mood disorders. 39, 40 In Rett Syndrome, a disorder in which severe symptoms affect cognitive, sensory, emotional, motor and autonomic functions, 5-HT 7 receptor agonist was shown to ameliorate the deficits in motor coordination, spatial reference memory, and hippocampal synaptic plasticity in a mice model. 41 Thus, the activation of 5-HT 7 receptor appears to restore synaptic plasticity, suggesting that agonists of this receptor might be used as novel pharmacological tools in both diseases.…”

Drug design of 5-substituted-2-aminotetralins targeting the serotonin 5-HT7 receptor

“…Genetic models of cognitive disorders also implicate 5-HT 7 as having procognitive effects. In Fmr1 KO mice, a model of fragile X syndrome (FXS), the 5-HT 7 agonist LP-211 reverses mGluR-dependent long-term depression 39,43 , while in Mecp2 KO mice, a model of Rett syndrome and autism spectrum disorder (ASD), LP-211 was able to correct memory impairments in a novelty preference task, a measurement of implicit/long-term memory 44 . While this evidence shows that 5-HT 7 can be a therapeutic target for cognitive dysfunction, it also shows that there is still more to be done in regard to distinguishing between pro-cognitive effects of 5-HT 7 activation vs. inactivation.…”

“…Patients with FXS show mood disorders, deficits in cognitive ability, and increased susceptibility to seizures. FXS is caused by a single deletion or mutation in the Fragile X Mental Retardation protein (Fmr1), which is important regulator of protein transcription 43,90 . The FXS phenotype has been linked to mGluR5 dependent long-term depression, leading to cognitive deficits, which have been rescued through activation of the 5-HT 7 receptor 43,91 .…”

“…FXS is caused by a single deletion or mutation in the Fragile X Mental Retardation protein (Fmr1), which is important regulator of protein transcription 43,90 . The FXS phenotype has been linked to mGluR5 dependent long-term depression, leading to cognitive deficits, which have been rescued through activation of the 5-HT 7 receptor 43,91 . The FXS phenotype also results in altered dendritic morphology in the hippocampus, where 5-HT 7 activation has shown to modulate neuronal development and morphology 92 .…”