{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T17:19:13Z","timestamp":1775841553403,"version":"3.50.1"},"reference-count":114,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T00:00:00Z","timestamp":1741651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MUR","award":["P2022XPAW4"],"award-info":[{"award-number":["P2022XPAW4"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The brain serotonin (5-HT) system modulates glutamatergic and GABAergic transmission in almost every brain area, crucially regulating mood, food intake, body temperature, pain, hormone secretion, learning and memory. Previous studies suggest a disruption of the brain 5-HT system in Fragile X Syndrome, with abnormal activity of the 5-HT transporter leading to altered 5-HT brain levels. We provide an update on therapeutic effects exerted by drugs modulating serotonergic transmission on Fragile X patients and animal models. The enhancement of serotonergic transmission using Selective Serotonin Reuptake Inhibitors (SSRIs) corrected mood disorders and language deficits in Fragile X patients. In Fmr1 KO mice, a model of Fragile X Syndrome, selective 5-HT7 receptor agonists rescued synaptic plasticity, memory and stereotyped behavior. In addition, drugs specifically acting on 5-HT1A, 5-HT2 and 5-HT5 receptor subtypes were able to correct, respectively, epilepsy, learning deficits and hyperactivity in different Fragile X animal models. In conclusion, the SSRI treatment of Fragile X patients improves mood and language; in parallel, studies on animal models suggest that compounds selectively acting on distinct 5-HT receptor subtypes might provide a targeted correction of other Fragile X phenotypes, and thus should be further tested in clinical trials for future therapy.<\/jats:p>","DOI":"10.3390\/ijms26062495","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T06:52:30Z","timestamp":1741675950000},"page":"2495","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Therapeutic Effects of Pharmacological Modulation of Serotonin Brain System in Human Patients and Animal Models of Fragile X Syndrome"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0274-6095","authenticated-orcid":false,"given":"Lucia","family":"Ciranna","sequence":"first","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2465-8080","authenticated-orcid":false,"given":"Lara","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0074-7742(04)59006-2","article-title":"Serotonin and brain development","volume":"59","author":"Sodhi","year":"2004","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.pneurobio.2016.03.007","article-title":"How serotonin receptors regulate morphogenic signalling in neurons","volume":"151","author":"Wirth","year":"2017","journal-title":"Prog. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S16","DOI":"10.1038\/sj.mp.4001167","article-title":"Role of altered brain serotonin mechanisms in autism","volume":"7","author":"Chugani","year":"2002","journal-title":"Mol. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.bbr.2008.03.020","article-title":"Molecular biology of 5-HT receptors","volume":"195","author":"Hannon","year":"2008","journal-title":"Behav. Brain Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.neuroscience.2014.07.070","article-title":"5-HT3A receptors are required in long-term depression and AMPA receptor internalization","volume":"278","author":"Yu","year":"2014","journal-title":"Neuroscience"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1523\/JNEUROSCI.15-03-02445.1995","article-title":"Effects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat","volume":"15","author":"Staubli","year":"1995","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/S0026-895X(25)10829-8","article-title":"Pharmacological characterization of 5-hydroxytryptamine4(5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: Effect of substituted benzamide derivatives","volume":"37","author":"Bockaert","year":"1990","journal-title":"Mol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/0014-2999(89)90304-X","article-title":"BRL 24924: A potent agonist at a non-classical 5-HT receptor positively coupled with adenylate cyclase in colliculi neurons","volume":"162","author":"Dumuis","year":"1989","journal-title":"Eur. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1038\/sj.npp.1301644","article-title":"The promnesic effect of G-protein-coupled 5-HT4 receptors activation is mediated by a potentiation of learning-induced spine growth in the mouse hippocampus","volume":"33","author":"Restivo","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.neuropharm.2004.06.033","article-title":"Modulation of memory processes and cellular excitability in the dentate gyrus of freely moving rats by a 5-HT4 receptors partial agonist, and an antagonist","volume":"47","author":"Marchetti","year":"2004","journal-title":"Neuropharmacology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.pharmthera.2005.12.006","article-title":"5-ht5A receptors as a therapeutic target","volume":"111","author":"Thomas","year":"2006","journal-title":"Pharmacol. Ther."},{"key":"ref_12","first-page":"371","article-title":"Serotonin receptors of type 6 (5-HT6): From neuroscience to clinical pharmacology","volume":"20","author":"Marazziti","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8547","DOI":"10.1073\/pnas.90.18.8547","article-title":"Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation","volume":"90","author":"Ruat","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/S0026-895X(25)13616-X","article-title":"Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs","volume":"43","author":"Monsma","year":"1993","journal-title":"Mol. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/0896-6273(93)90149-L","article-title":"A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms","volume":"11","author":"Lovenberg","year":"1993","journal-title":"Neuron"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.tips.2004.07.002","article-title":"Functional, molecular and pharmacological advances in 5-HT7 receptor research","volume":"25","author":"Hedlund","year":"2004","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/sj.bjp.0705576","article-title":"Autoradiographic distribution of 5-HT7 receptors in the human brain using [3H]mesulergine: Comparison to other mammalian species","volume":"141","author":"Pazos","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.neulet.2004.06.025","article-title":"Distribution of 5-HT7 receptors in the human brain: A preliminary autoradiographic study using [3H]SB-269970","volume":"367","author":"Varnas","year":"2004","journal-title":"Neurosci. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23422","DOI":"10.1016\/S0021-9258(19)49479-9","article-title":"Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase","volume":"268","author":"Bard","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1074\/jbc.M206237200","article-title":"Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a)","volume":"278","author":"Norum","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1046\/j.1471-4159.2003.02076.x","article-title":"Coupling of neuronal 5-HT7 receptors to activation of extracellular-regulated kinase through a protein kinase A-independent pathway that can utilize Epac","volume":"87","author":"Lin","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/S0306-4522(00)00460-7","article-title":"5-HT(7) receptors activate the mitogen activated protein kinase extracellular signal related kinase in cultured rat hippocampal neurons","volume":"102","author":"Errico","year":"2001","journal-title":"Neuroscience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1113\/jphysiol.2010.201657","article-title":"Spinal 5-HT7 receptor activation induces long-lasting phrenic motor facilitation","volume":"589","author":"Hoffman","year":"2011","journal-title":"J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/j.1471-4159.2004.02832.x","article-title":"Enhanced activation of Akt and extracellular-regulated kinase pathways by simultaneous occupancy of Gq-coupled 5-HT2A receptors and Gs-coupled 5-HT7A receptors in PC12 cells","volume":"92","author":"Kertesy","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7821","DOI":"10.1523\/JNEUROSCI.1790-05.2005","article-title":"5-HT7 receptor is coupled to G alpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology","volume":"25","author":"Kvachnina","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1126\/science.280.5372.2074","article-title":"G proteins and small GTPases: Distant relatives keep in touch","volume":"280","author":"Hall","year":"1998","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1007\/s12035-011-8175-3","article-title":"Role of the 5-HT7 receptor in the central nervous system: From current status to future perspectives","volume":"43","author":"Matthys","year":"2011","journal-title":"Mol. Neurobiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1523\/JNEUROSCI.2765-11.2012","article-title":"5-HT7R\/G12 signaling regulates neuronal morphology and function in an age-dependent manner","volume":"32","author":"Kobe","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Speranza, L., Giuliano, T., Volpicelli, F., De Stefano, M.E., Lombardi, L., Chambery, A., Lacivita, E., Leopoldo, M., Bellenchi, G.C., and di Porzio, U. (2015). Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics. Front. Behav. Neurosci., 9.","DOI":"10.3389\/fnbeh.2015.00062"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1007\/s00213-014-3693-0","article-title":"5-HT7 receptor activation: Procognitive and antiamnesic effects","volume":"232","author":"Meneses","year":"2015","journal-title":"Psychopharmacology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1016\/j.neuropharm.2012.06.061","article-title":"5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: Implications for effects of selective serotonin reuptake inhibitors","volume":"63","author":"Eriksson","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ciranna, L., and Catania, M.V. (2014). 5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: Physiological role and possible implications in autism spectrum disorders. Front. Cell Neurosci., 8.","DOI":"10.3389\/fncel.2014.00250"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"R273","DOI":"10.1016\/j.cub.2021.01.043","article-title":"Fragile X syndrome","volume":"31","author":"Hagerman","year":"2021","journal-title":"Curr. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.neuropharm.2012.11.028","article-title":"Fragile X syndrome: From targets to treatments","volume":"68","author":"Wijetunge","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5395","DOI":"10.1073\/pnas.94.10.5395","article-title":"Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation","volume":"94","author":"Weiler","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pfeiffer, B.E., and Huber, K.M. The State of Synapses in Fragile X Syndrome. Neuroscientist, 2009.","DOI":"10.1177\/1073858409333075"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S1462399406010751","article-title":"The fragile X syndrome: Exploring its molecular basis and seeking a treatment","volume":"8","author":"Bardoni","year":"2006","journal-title":"Expert. Rev. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/1096-8628(20010115)98:2<161::AID-AJMG1025>3.0.CO;2-B","article-title":"Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: A quantitative examination","volume":"98","author":"Irwin","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5401","DOI":"10.1073\/pnas.94.10.5401","article-title":"Abnormal dendritic spines in fragile X knockout mice: Maturation and pruning deficits","volume":"94","author":"Comery","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7746","DOI":"10.1073\/pnas.122205699","article-title":"Altered synaptic plasticity in a mouse model of fragile X mental retardation","volume":"99","author":"Huber","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.tins.2004.04.009","article-title":"The mGluR theory of fragile X mental retardation","volume":"27","author":"Bear","year":"2004","journal-title":"Trends Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8908","DOI":"10.1523\/JNEUROSCI.0932-05.2005","article-title":"A reduced number of metabotropic glutamate subtype 5 receptors are associated with constitutive homer proteins in a mouse model of fragile X syndrome","volume":"25","author":"Giuffrida","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1038\/s41467-017-01191-2","article-title":"Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice","volume":"8","author":"Aloisi","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/jnr.22546","article-title":"Fragile X mice: Reduced long-term potentiation and N-Methyl-D-Aspartate receptor-mediated neurotransmission in dentate gyrus","volume":"89","author":"Yun","year":"2011","journal-title":"J. Neurosci. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.neuroscience.2012.06.052","article-title":"Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse","volume":"221","author":"Gocel","year":"2012","journal-title":"Neuroscience"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1093\/cercor\/bht237","article-title":"Rescue of NMDAR-Dependent Synaptic Plasticity in Fmr1 Knock-Out Mice","volume":"25","author":"Bostrom","year":"2015","journal-title":"Cereb. Cortex"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2174\/1570159X113116660046","article-title":"The role of ionotropic glutamate receptors in childhood neurodevelopmental disorders: Autism spectrum disorders and fragile x syndrome","volume":"12","author":"Uzunova","year":"2014","journal-title":"Curr. Neuropharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.brainres.2006.08.115","article-title":"Decreased expression of the GABAA receptor in fragile X syndrome","volume":"1121","author":"Reeve","year":"2006","journal-title":"Brain Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1093\/cercor\/bhn159","article-title":"Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome","volume":"19","author":"Curia","year":"2009","journal-title":"Cereb. Cortex"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.neuropharm.2014.06.028","article-title":"Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials","volume":"88","author":"Braat","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1152\/jn.00597.2013","article-title":"Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala","volume":"112","author":"Martin","year":"2014","journal-title":"J. Neurophysiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/ejhg.2008.61","article-title":"Fragile X syndrome","volume":"16","author":"Garber","year":"2008","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1100\/tsw.2006.220","article-title":"Fmr1 KO mice as a possible model of autistic features","volume":"6","author":"Bernardet","year":"2006","journal-title":"Sci. World J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"110","DOI":"10.5582\/irdr.2014.01027","article-title":"Serotonin dysregulation in Fragile X Syndrome: Implications for treatment","volume":"3","author":"Hanson","year":"2014","journal-title":"Intractable Rare Dis. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1007\/s10803-007-0365-5","article-title":"Brief report: Aggression and stereotypic behavior in males with fragile X syndrome--moderating secondary genes in a \u201csingle gene\u201d disorder","volume":"38","author":"Hessl","year":"2008","journal-title":"J. Autism Dev. Disord."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"McCarthy, D.M., Vied, C., Trupiano, M.X., Canekeratne, A.J., Wang, Y., Schatschneider, C., and Bhide, P.G. (2024). Behavioral, neurotransmitter and transcriptomic analyses in male and female Fmr1 KO mice. Front. Behav. Neurosci., 18.","DOI":"10.3389\/fnbeh.2024.1458502"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Uutela, M., Lindholm, J., Rantamaki, T., Umemori, J., Hunter, K., Voikar, V., and Castren, M.L. (2014). Distinctive behavioral and cellular responses to fluoxetine in the mouse model for Fragile X syndrome. Front. Cell Neurosci., 8.","DOI":"10.3389\/fncel.2014.00150"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Quinlan, M.A., Robson, M.J., Ye, R., Rose, K.L., Schey, K.L., and Blakely, R.D. (2020). Ex vivo Quantitative Proteomic Analysis of Serotonin Transporter Interactome: Network Impact of the SERT Ala56 Coding Variant. Front. Mol. Neurosci., 13.","DOI":"10.3389\/fnmol.2020.00089"},{"key":"ref_59","first-page":"280813","article-title":"Early intervention combined with targeted treatment promotes cognitive and behavioral improvements in young children with fragile x syndrome","volume":"2012","author":"Winarni","year":"2012","journal-title":"Case Rep. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1097\/DBP.0000000000000334","article-title":"A Randomized, Double-Blind, Placebo-Controlled Trial of Low-Dose Sertraline in Young Children With Fragile X Syndrome","volume":"37","author":"Fitzpatrick","year":"2016","journal-title":"J. Dev. Behav. Pediatr."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Rajaratnam, A., Potter, L.A., Biag, H.M.B., Schneider, A., Petrasic, I.C., and Hagerman, R.J. (2020). Review of Autism Profiles and Response to Sertraline in Fragile X Syndrome-Associated Autism vs. Non-syndromic Autism; Next Steps for Targeted Treatment. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.581429"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.braindev.2017.01.012","article-title":"Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome","volume":"39","author":"AlOlaby","year":"2017","journal-title":"Brain Dev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1021\/acsptsci.9b00101","article-title":"(S)-5-(2\u2032-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder","volume":"3","author":"Armstrong","year":"2020","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3629","DOI":"10.1021\/acschemneuro.2c00574","article-title":"FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT(1A), 5-HT(1B), and 5-HT(1D) Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice","volume":"13","author":"Saraf","year":"2022","journal-title":"ACS Chem. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.neuroscience.2022.11.014","article-title":"Acute and Repeated Administration of NLX-101, a Selective Serotonin-1A Receptor Biased Agonist, Reduces Audiogenic Seizures in Developing Fmr1 Knockout Mice","volume":"509","author":"Tao","year":"2023","journal-title":"Neuroscience"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"109774","DOI":"10.1016\/j.neuropharm.2023.109774","article-title":"Altered brain serotonin 5-HT(1A) receptor expression and function in juvenile Fmr1 knockout mice","volume":"245","author":"Saraf","year":"2024","journal-title":"Neuropharmacology"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Vannelli, A., Mariano, V., Bagni, C., and Kanellopoulos, A.K. (2024). Activation of the 5-HT1A Receptor by Eltoprazine Restores Mitochondrial and Motor Deficits in a Drosophila Model of Fragile X Syndrome. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168787"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1101\/gad.232470.113","article-title":"Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model","volume":"28","author":"Lim","year":"2014","journal-title":"Genes. Dev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1093\/ijnp\/pyac041","article-title":"5-HT5A Receptor Antagonist ASP5736 Ameliorates Several Abnormal Behaviors in an Fmr1-Targeted Transgenic Male Rat Model of Fragile X Syndrome","volume":"25","author":"Yamazaki","year":"2022","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/j.biopsych.2012.06.008","article-title":"Activation of 5-HT7 serotonin receptors reverses metabotropic glutamate receptor-mediated synaptic plasticity in wild-type and Fmr1 knockout mice, a model of Fragile X syndrome","volume":"72","author":"Costa","year":"2012","journal-title":"Biol. Psychiatry"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Costa, L., Sardone, L.M., Lacivita, E., Leopoldo, M., and Ciranna, L. (2015). 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. Front. Behav. Neurosci., 9.","DOI":"10.3389\/fnbeh.2015.00065"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Costa, L., Sardone, L.M., Bonaccorso, C.M., D\u2019Antoni, S., Spatuzza, M., Gulisano, W., Tropea, M.R., Puzzo, D., Leopoldo, M., and Lacivita, E. (2018). Activation of Serotonin 5-HT7 Receptors Modulates Hippocampal Synaptic Plasticity by Stimulation of Adenylate Cyclases and Rescues Learning and Behavior in a Mouse Model of Fragile X Syndrome. Front. Mol. Neurosci., 11.","DOI":"10.3389\/fnmol.2018.00353"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Sharghi, S., Flunkert, S., Daurer, M., Rabl, R., Chagnaud, B.P., Leopoldo, M., Lacivita, E., Hutter-Paier, B., and Prokesch, M. (2023). Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and Fmr1-KO mouse models. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1087788"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/sj.bjp.0703357","article-title":"Characterization of SB-269970-A, a selective 5-HT(7) receptor antagonist","volume":"130","author":"Hagan","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1002\/hipo.20940","article-title":"5-HT(1A) and 5-HT(7) receptors differently modulate AMPA receptor-mediated hippocampal synaptic transmission","volume":"22","author":"Costa","year":"2012","journal-title":"Hippocampus"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/ajmg.1320450120","article-title":"Demonstration of abnormal cyclic AMP production in platelets from patients with fragile X syndrome","volume":"45","author":"Sklena","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/ana.410310105","article-title":"Cyclic AMP metabolism in fragile X syndrome","volume":"31","author":"Huttenlocher","year":"1992","journal-title":"Ann. Neurol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Kelley, D.J., Davidson, R.J., Elliott, J.L., Lahvis, G.P., Yin, J.C., and Bhattacharyya, A. (2007). The cyclic AMP cascade is altered in the fragile X nervous system. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000931"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"6344","DOI":"10.1093\/nar\/gky267","article-title":"HITS-CLIP in various brain areas reveals new targets and new modalities of RNA binding by fragile X mental retardation protein","volume":"46","author":"Maurin","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1093\/cercor\/bhy192","article-title":"Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome","volume":"29","author":"Maurin","year":"2019","journal-title":"Cereb. Cortex"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4124","DOI":"10.1111\/ejn.15246","article-title":"Serotonin 5-HT7 receptors require cyclin-dependent kinase 5 to rescue hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome","volume":"54","author":"Costa","year":"2021","journal-title":"Eur. J. Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Pao, P.C., and Tsai, L.H. (2021). Three decades of Cdk5. J. Biomed. Sci., 28.","DOI":"10.1186\/s12929-021-00774-y"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Ao, C., Li, C., Chen, J., Tan, J., and Zeng, L. (2022). The role of Cdk5 in neurological disorders. Front. Cell Neurosci., 16.","DOI":"10.3389\/fncel.2022.951202"},{"key":"ref_84","first-page":"813","article-title":"Identification of differentially expressed microRNAs and their target genes in the hippocampal tissues of Fmr1 knockout mice","volume":"12","author":"Zhang","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Lin, L., Hu, X., Hong, W., Pan, T., Wang, Z., Wang, E., and Wu, G. (2024). A novel animal model of spontaneous epilepsy: Cdk5 knockout in pericyte-specific mice. Front. Cell Neurosci., 18.","DOI":"10.3389\/fncel.2024.1474231"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"113866","DOI":"10.1016\/j.expneurol.2021.113866","article-title":"Lack of Cdk5 activity is involved on Dopamine Transporter expression and function: Evidences from an animal model of Attention-Deficit Hyperactivity Disorder","volume":"346","author":"Fernandez","year":"2021","journal-title":"Exp. Neurol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neulet.2010.06.036","article-title":"LP-211 is a brain penetrant selective agonist for the serotonin 5-HT(7) receptor","volume":"481","author":"Hedlund","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1046\/j.1460-9568.2000.00007.x","article-title":"The serotonin 5-HT2 receptor-phospholipase C system inhibits the induction of long-term potentiation in the rat visual cortex","volume":"12","author":"Edagawa","year":"2000","journal-title":"Eur. J. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Xu, Z.H., Yang, Q., Ma, L., Liu, S.B., Chen, G.S., Wu, Y.M., Li, X.Q., Liu, G., and Zhao, M.G. (2012). Deficits in LTP induction by 5-HT2A receptor antagonist in a mouse model for fragile X syndrome. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048741"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S0006-8993(99)01300-1","article-title":"Stimulation of the 5-HT1A receptor selectively suppresses NMDA receptor-mediated synaptic excitation in the rat visual cortex","volume":"827","author":"Edagawa","year":"1999","journal-title":"Brain Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/S0278-5846(98)00055-4","article-title":"Serotonin inhibits the induction of long-term potentiation in rat primary visual cortex","volume":"22","author":"Edagawa","year":"1998","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1021\/acschemneuro.5b00099","article-title":"An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist that Corrects Motor Stereotypy in Mouse Models","volume":"6","author":"Canal","year":"2015","journal-title":"ACS Chem. Neurosci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"548","DOI":"10.2119\/molmed.2016.00122","article-title":"Altered redox mitochondrial biology in the neurodegenerative disorder fragile X-tremor\/ataxia syndrome: Use of antioxidants in precision medicine","volume":"22","author":"Song","year":"2016","journal-title":"Mol. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s41593-019-0338-y","article-title":"Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice","volume":"22","author":"Shen","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1515\/hsz-2019-0221","article-title":"Aberrant mitochondrial bioenergetics in the cerebral cortex of the Fmr1 knockout mouse model of fragile X syndrome","volume":"401","author":"Valenti","year":"2020","journal-title":"Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"7404","DOI":"10.1096\/fj.202000283RR","article-title":"Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome","volume":"34","author":"Griffiths","year":"2020","journal-title":"FASEB J."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.jphs.2015.02.006","article-title":"Novel 5-HT5A receptor antagonists ameliorate scopolamine-induced working memory deficit in mice and reference memory impairment in aged rats","volume":"127","author":"Yamazaki","year":"2015","journal-title":"J. Pharmacol. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.euroneuro.2018.03.003","article-title":"Functional mechanism of ASP5736, a selective serotonin 5-HT(5A) receptor antagonist with potential utility for the treatment of cognitive dysfunction in schizophrenia","volume":"28","author":"Yamazaki","year":"2018","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1016\/j.euroneuro.2014.07.009","article-title":"ASP5736, a novel 5-HT5A receptor antagonist, ameliorates positive symptoms and cognitive impairment in animal models of schizophrenia","volume":"24","author":"Yamazaki","year":"2014","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/npp.2017.177","article-title":"Effect of the mGluR5-NAM Basimglurant on Behavior in Adolescents and Adults with Fragile X Syndrome in a Randomized, Double-Blind, Placebo-Controlled Trial: FragXis Phase 2 Results","volume":"43","author":"Youssef","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Hagerman, R., Jacquemont, S., Berry-Kravis, E., Des Portes, V., Stanfield, A., Koumaras, B., Rosenkranz, G., Murgia, A., Wolf, C., and Apostol, G. (2018). Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-34978-4"},{"key":"ref_102","first-page":"321ra325","article-title":"Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials","volume":"8","author":"Hagerman","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s11689-017-9207-8","article-title":"A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome","volume":"9","author":"Ligsay","year":"2017","journal-title":"J. Neurodev. Disord."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s11689-016-9181-6","article-title":"Arbaclofen in fragile X syndrome: Results of phase 3 trials","volume":"9","author":"Hagerman","year":"2017","journal-title":"J. Neurodev. Disord."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/s41591-021-01321-w","article-title":"Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: A randomized, placebo-controlled, phase 2 clinical trial","volume":"27","author":"Harnett","year":"2021","journal-title":"Nat. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1002\/aur.3222","article-title":"Neurophysiological effects of a combined treatment of lovastatin and minocycline in patients with fragile X syndrome: Ancillary results of the LOVAMIX randomized clinical trial","volume":"17","author":"Champigny","year":"2024","journal-title":"Autism Res."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Proteau-Lemieux, M., Lacroix, A., Galarneau, L., Corbin, F., Lepage, J.F., and Caku, A. (2021). The safety and efficacy of metformin in fragile X syndrome: An open-label study. Prog. Neuropsychopharmacol. Biol. Psychiatry, 110.","DOI":"10.1016\/j.pnpbp.2021.110307"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Seng, P., Montanaro, F.A.M., Biag, H.M.B., Salcedo-Arellano, M.J., Kim, K., Ponzini, M.D., Tassone, F., Schneider, A., Abbeduto, L., and Thurman, A.J. (2024). Longitudinal follow-up of metformin treatment in Fragile X Syndrome. Front. Psychol., 15.","DOI":"10.3389\/fpsyg.2024.1305597"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.brainres.2012.04.032","article-title":"Buspirone: What is it all about?","volume":"1461","author":"Loane","year":"2012","journal-title":"Brain Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1021\/acschemneuro.7b00087","article-title":"Classics in Chemical Neuroscience: Aripiprazole","volume":"8","author":"Casey","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"4595","DOI":"10.1007\/s10803-019-04173-z","article-title":"Pharmacologic Interventions for Irritability, Aggression, Agitation and Self-Injurious Behavior in Fragile X Syndrome: An Initial Cross-Sectional Analysis","volume":"49","author":"Eckert","year":"2019","journal-title":"J. Autism Dev. Disord."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s11920-021-01298-w","article-title":"New Antipsychotic Medications in the Last Decade","volume":"23","author":"Pahwa","year":"2021","journal-title":"Curr. Psychiatry Rep."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"112395","DOI":"10.1016\/j.ejmech.2020.112395","article-title":"Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target Fragile X syndrome","volume":"199","author":"Lacivita","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1021\/acschemneuro.0c00647","article-title":"Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder","volume":"12","author":"Lacivita","year":"2021","journal-title":"ACS Chem. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/6\/2495\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:50:32Z","timestamp":1760028632000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/6\/2495"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,11]]},"references-count":114,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26062495"],"URL":"https:\/\/doi.org\/10.3390\/ijms26062495","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,11]]}}}