{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:19:05Z","timestamp":1790752745938,"version":"4.1.0"},"reference-count":103,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GW Pharmaceutical (Cambridge, UK)"},{"name":"CNRS"},{"name":"University of Bordeaux"},{"name":"SUNY Downstate University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Phytocannabinoids, including the non-addictive cannabis component cannabidivarin (CBDV), have been reported to hold therapeutic potential in several neurodevelopmental disorders (NDDs). Nonetheless, the therapeutic value of phytocannabinoids for treating Fragile X syndrome (FXS), a major NDD, remains unexplored. Here, we characterized the neurobehavioral effects of CBDV at doses of 20 or 100 mg\/kg in the Fmr1-knockout (Fmr1-KO) mouse model of FXS using two temporally different intraperitoneal regimens: subchronic 10-day delivery during adulthood (Study 1: rescue treatment) or chronic 5-week delivery at adolescence (Study 2: preventive treatment). Behavioral tests assessing FXS-like abnormalities included anxiety, locomotor, cognitive, social and sensory alterations. Expression of inflammatory and plasticity markers was investigated in the hippocampus and prefrontal cortex. When administered during adulthood (Study 1), the effects of CBDV were marginal, rescuing at the lower dose only the acoustic hyper-responsiveness of Fmr1-KO mice and at both doses their altered hippocampal expression of neurotrophins. When administered during adolescence (Study 2), CBDV at both doses prevented the cognitive, social and acoustic alterations of adult Fmr1-KO mice and modified the expression of several inflammatory brain markers in both wild-type littermates and mutants. These findings warrant the therapeutic potential of CBDV for preventing neurobehavioral alterations associated with FXS, highlighting the relevance of its early administration.<\/jats:p>","DOI":"10.3390\/cells12151927","type":"journal-article","created":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T01:03:25Z","timestamp":1690333405000},"page":"1927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Early Administration of the Phytocannabinoid Cannabidivarin Prevents the Neurobehavioral Abnormalities Associated with the Fmr1-KO Mouse Model of Fragile X Syndrome"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2948-7524","authenticated-orcid":false,"given":"Marika","family":"Premoli","sequence":"first","affiliation":[{"name":"CNRS, EPHE, INCIA, UMR 5287, Univ. Bordeaux, 33000 Bordeaux, France"},{"name":"Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8389-9899","authenticated-orcid":false,"given":"William","family":"Fyke","sequence":"additional","affiliation":[{"name":"CNRS, EPHE, INCIA, UMR 5287, Univ. Bordeaux, 33000 Bordeaux, France"},{"name":"Graduate Program in Neural and Behavioral Science, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Bellocchio","sequence":"additional","affiliation":[{"name":"INSERM, U1215 NeuroCentre Magendie, Group Endocannabinoids and Neuroadaptation, University of Bordeaux, 33077 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Lemaire","sequence":"additional","affiliation":[{"name":"CNRS, EPHE, INCIA, UMR 5287, Univ. Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Wolley-Roberts","sequence":"additional","affiliation":[{"name":"Jazz Pharmaceuticals, Inc., Cambridge OX4 2RW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Bontempi","sequence":"additional","affiliation":[{"name":"CNRS, EPHE, INCIA, UMR 5287, Univ. Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8993-1922","authenticated-orcid":false,"given":"Susanna","family":"Pietropaolo","sequence":"additional","affiliation":[{"name":"CNRS, EPHE, INCIA, UMR 5287, Univ. Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.expneurol.2010.03.018","article-title":"The Endocannabinoid System and Psychiatric Disorders","volume":"224","author":"Parolaro","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/3-540-26573-2_10","article-title":"Distribution of Cannabinoid Receptors in the Central and Peripheral Nervous System","volume":"168","author":"Mackie","year":"2005","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"448","DOI":"10.2174\/138955709787847921","article-title":"Endocannabinoid System: Emerging Role from Neurodevelopment to Neurodegeneration","volume":"9","author":"Basavarajappa","year":"2009","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1126\/science.1137406","article-title":"Hardwiring the Brain: Endocannabinoids Shape Neuronal Connectivity","volume":"316","author":"Berghuis","year":"2007","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.neuron.2006.07.006","article-title":"The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus","volume":"51","author":"Monory","year":"2006","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.neuropharm.2018.07.029","article-title":"Chronic Treatment with the Phytocannabinoid Cannabidivarin (Cbdv) Rescues Behavioural Alterations and Brain Atrophy in a Mouse Model of Rett Syndrome","volume":"140","author":"Vigli","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1177\/0269881119844184","article-title":"Cannabidivarin Completely Rescues Cognitive Deficits and Delays Neurological and Motor Defects in Male Mecp2 Mutant Mice","volume":"33","author":"Zamberletti","year":"2019","journal-title":"J. Psychopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e72560","DOI":"10.7554\/eLife.72560","article-title":"Cannabinoid Signaling Modulation through Jzl184 Restores Key Phenotypes of a Mouse Model for Williams-Beuren Syndrome","volume":"11","author":"Pastor","year":"2022","journal-title":"Elife"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nm.3127","article-title":"Targeting the Endocannabinoid System in the Treatment of Fragile X Syndrome","volume":"19","author":"Guegan","year":"2013","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1038\/ncomms2045","article-title":"Uncoupling of the Endocannabinoid Signalling Complex in a Mouse Model of Fragile X Syndrome","volume":"3","author":"Jung","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1038\/npp.2010.19","article-title":"Abnormal Mglu 5 Receptor\/Endocannabinoid Coupling in Mice Lacking Fmrp and Bc1 Rna","volume":"35","author":"Maccarrone","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5724","DOI":"10.1523\/JNEUROSCI.0795-10.2010","article-title":"Enhanced Endocannabinoid Signaling Elevates Neuronal Excitability in Fragile X Syndrome","volume":"30","author":"Zhang","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/0092-8674(91)90125-I","article-title":"Absence of Expression of the Fmr-1 Gene in Fragile X Syndrome","volume":"66","author":"Pieretti","year":"1991","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/0092-8674(91)90397-H","article-title":"Identification of a Gene (Fmr-1) Containing a Cgg Repeat Coincident with a Breakpoint Cluster Region Exhibiting Length Variation in Fragile X Syndrome","volume":"65","author":"Verkerk","year":"1991","journal-title":"Cell"},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.biopsych.2013.05.038","article-title":"Chronic Metabotropic Glutamate Receptor 5 Inhibition Corrects Local Alterations of Brain Activity and Improves Cognitive Performance in Fragile X Mice","volume":"75","author":"Michalon","year":"2014","journal-title":"Biol. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/j.1601-183X.2012.00768.x","article-title":"Altered Mtor Signaling and Enhanced Cyfip2 Expression Levels in Subjects with Fragile X Syndrome","volume":"11","author":"Hoeffer","year":"2012","journal-title":"Genes Brain Behav."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13958","DOI":"10.1523\/JNEUROSCI.4383-07.2007","article-title":"Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of Mglur1\/5 and Mtor","volume":"27","author":"Price","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1523\/JNEUROSCI.3696-09.2010","article-title":"Dysregulation of Mtor Signaling in Fragile X Syndrome","volume":"30","author":"Sharma","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1152\/physrev.00019.2008","article-title":"Endocannabinoid-Mediated Control of Synaptic Transmission","volume":"89","author":"Kano","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"RC188","DOI":"10.1523\/JNEUROSCI.21-24-j0003.2001","article-title":"Metabotropic Glutamate Receptors Drive the Endocannabinoid System in Hippocampus","volume":"21","author":"Varma","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1098\/rstb.2011.0384","article-title":"Cellular and Intracellular Mechanisms Involved in the Cognitive Impairment of Cannabinoids","volume":"367","author":"Puighermanal","year":"2012","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1038\/nn.2369","article-title":"Cannabinoid Modulation of Hippocampal Long-Term Memory Is Mediated by Mtor Signaling","volume":"12","author":"Puighermanal","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_24","unstructured":"Pietropaolo, S., Bellocchio, L., Oddi, D., D\u2019Amato, F.R., Marsicano, G., and Crusio, W.E. (2010, January 3\u20137). The Fmr1 Mouse Line as a Model for Autism: The Relevance of the Genetic Background and of the Endocannabinoid System. Proceedings of the FENS Annual Meeting, Amsterdam, The Netherlands."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.biocel.2014.05.004","article-title":"New Insights into the Molecular Pathophysiology of Fragile X Syndrome and Therapeutic Perspectives from the Animal Model","volume":"53","author":"Maldonado","year":"2014","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1083\/jcb.200305129","article-title":"Cloning of the First Sn1-Dag Lipases Points to the Spatial and Temporal Regulation of Endocannabinoid Signaling in the Brain","volume":"163","author":"Bisogno","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s13311-015-0387-1","article-title":"Cannabidiol as a Potential Treatment for Anxiety Disorders","volume":"12","author":"Blessing","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/j.bmc.2015.01.059","article-title":"Cannabidiol (Cbd) and Its Analogs: A Review of Their Effects on Inflammation","volume":"23","author":"Burstein","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.phrs.2016.01.033","article-title":"Cannabidiol, Neuroprotection and Neuropsychiatric Disorders","volume":"112","author":"Campos","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5852","DOI":"10.18632\/oncotarget.2233","article-title":"Cannabinoids as Therapeutic Agents in Cancer: Current Status and Future Implications","volume":"5","author":"Chakravarti","year":"2014","journal-title":"Oncotarget"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1002\/phar.1780","article-title":"Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents","volume":"36","author":"Fasinu","year":"2016","journal-title":"Pharmacotherapy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.pharmthera.2011.09.002","article-title":"Phytocannabinoids as Novel Therapeutic Agents in Cns Disorders","volume":"133","author":"Hill","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1111\/j.1476-5381.2012.02207.x","article-title":"Cannabidivarin Is Anticonvulsant in Mouse and Rat","volume":"167","author":"Hill","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s00213-011-2415-0","article-title":"Plasma and Brain Pharmacokinetic Profile of Cannabidiol (Cbd), Cannabidivarine (Cbdv), Delta(9)-Tetrahydrocannabivarin (Thcv) and Cannabigerol (Cbg) in Rats and Mice Following Oral and Intraperitoneal Administration and Cbd Action on Obsessive-Compulsive Behaviour","volume":"219","author":"Deiana","year":"2012","journal-title":"Psychopharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"367","DOI":"10.3389\/fncel.2019.00367","article-title":"Cannabidivarin Treatment Ameliorates Autism-Like Behaviors and Restores Hippocampal Endocannabinoid System and Glia Alterations Induced by Prenatal Valproic Acid Exposure in Rats","volume":"13","author":"Zamberletti","year":"2019","journal-title":"Front. Cell Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pietropaolo, S., Sluyter, F., and Crusio, W.E. (2014). Behavioral Genetics of the Mouse, Cambridge University Press.","DOI":"10.1017\/CBO9781107360556"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S0149-7634(00)00014-2","article-title":"The Adolescent Brain and Age-Related Behavioral Manifestations","volume":"24","author":"Spear","year":"2000","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13023-014-0124-6","article-title":"Rescue of Fragile X Syndrome Phenotypes in Fmr1 Ko Mice by a Bkca Channel Opener Molecule","volume":"9","author":"Hebert","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/npp.2014.291","article-title":"Early Social Enrichment Rescues Adult Behavioral and Brain Abnormalities in a Mouse Model of Fragile X Syndrome","volume":"40","author":"Oddi","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.psyneuen.2014.07.002","article-title":"Dietary Supplementation of Omega-3 Fatty Acids Rescues Fragile X Phenotypes in Fmr1-Ko Mice","volume":"49","author":"Pietropaolo","year":"2014","journal-title":"Psychoneuroendocrinology"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Pietropaolo, S., Guilleminot, A., Martin, B., D\u2019Amato, F.R., and Crusio, W.E. (2011). Genetic-Background Modulation of Core and Variable Autistic-Like Symptoms in Fmr1 Knock-out Mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017073"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1038\/nn.3864","article-title":"Dendritic Channelopathies Contribute to Neocortical and Sensory Hyperexcitability in Fmr1(-\/Y) Mice","volume":"17","author":"Zhang","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1139\/o99-035","article-title":"Biology of the Fragile X Mental Retardation Protein, an Rna-Binding Protein","volume":"77","author":"Khandjian","year":"1999","journal-title":"Biochem. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1006\/excr.2000.4932","article-title":"Immunocytochemical and Biochemical Characterization of Fmrp, Fxr1p, and Fxr2p in the Mouse","volume":"258","author":"Bakker","year":"2000","journal-title":"Exp. Cell Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Dutch-Belgian Fragile X Consortium (1994). Fmr1 Knockout Mice: A Model to Study Fragile X Mental Retardation. Cell, 78, 23\u201333.","DOI":"10.1016\/0092-8674(94)90569-X"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1006\/anbe.2000.1504","article-title":"Ultrasonic Vocalization by Female Mice in the Presence of a Conspecific Carrying Food Cues","volume":"60","author":"Moles","year":"2000","journal-title":"Anim. Behav."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1002\/aur.1814","article-title":"Behavioral Abnormalities in the Fmr1-Ko2 Mouse Model of Fragile X Syndrome: The Relevance of Early Life Phases","volume":"10","author":"Gaudissard","year":"2017","journal-title":"Autism Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1002\/aur.1743","article-title":"Age-Specific Autistic-Like Behaviors in Heterozygous Fmr1-Ko Female Mice","volume":"10","author":"Gauducheau","year":"2017","journal-title":"Autism Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s10519-009-9291-y","article-title":"Strain-Dependent Changes in Acoustic Startle Response and Its Plasticity across Adolescence in Mice","volume":"39","author":"Pietropaolo","year":"2009","journal-title":"Behav. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1373\/clinchem.2008.112797","article-title":"The Miqe Guidelines: Minimum Information for Publication of Quantitative Real-Time Pcr Experiments","volume":"55","author":"Bustin","year":"2009","journal-title":"Clin. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative Pcr and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1016\/j.neurobiolaging.2012.10.006","article-title":"Working Memory Deficits and Related Disinhibition of the Camp\/Pka\/Creb Are Alleviated by Prefrontal Alpha4beta2 *-Nachrs Stimulation in Aged Mice","volume":"34","author":"Vandesquille","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"104722","DOI":"10.1016\/j.neubiorev.2022.104722","article-title":"Translational Validity and Methodological Underreporting in Animal Research: A Systematic Review and Meta-Analysis of the Fragile X Syndrome (Fmr1 Ko) Rodent Model","volume":"139","author":"Kat","year":"2022","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.neuron.2012.07.022","article-title":"Genetic Removal of P70 S6 Kinase 1 Corrects Molecular, Synaptic, and Behavioral Phenotypes in Fragile X Syndrome Mice","volume":"76","author":"Bhattacharya","year":"2012","journal-title":"Neuron"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.bbr.2009.11.019","article-title":"Altered Neuroligin Expression Is Involved in Social Deficits in a Mouse Model of the Fragile X Syndrome","volume":"208","author":"Dahlhaus","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1038\/npp.2008.152","article-title":"Alpha-Tocopherol Protects against Oxidative Stress in the Fragile X Knockout Mouse: An Experimental Therapeutic Approach for the Fmr1 Deficiency","volume":"34","author":"Decara","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.nbd.2009.08.001","article-title":"Fmr1 Knockout Mice Show Reduced Anxiety and Alterations in Neurogenesis That Are Specific to the Ventral Dentate Gyrus","volume":"36","author":"Eadie","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11489","DOI":"10.1073\/pnas.0705003104","article-title":"Inhibition of P21-Activated Kinase Rescues Symptoms of Fragile X Syndrome in Mice","volume":"104","author":"Hayashi","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S1461145710000520","article-title":"Lithium Ameliorates Phenotypic Deficits in a Mouse Model of Fragile X Syndrome","volume":"14","author":"Liu","year":"2011","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1002\/hipo.10005","article-title":"Behavioral and Neuroanatomical Characterization of the Fmr1 Knockout Mouse","volume":"12","author":"Mineur","year":"2002","journal-title":"Hippocampus"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1159\/000332884","article-title":"The Gaba(a) Receptor Agonist Thip Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome","volume":"33","author":"Corbin","year":"2011","journal-title":"Dev. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1093\/hmg\/9.8.1145","article-title":"(Over) Correction of Fmr1 Deficiency with Yac Transgenics: Behavioral and Physical Features","volume":"9","author":"Peier","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"11557","DOI":"10.1073\/pnas.0504984102","article-title":"Enriched Environment Promotes Behavioral and Morphological Recovery in a Mouse Model for the Fragile X Syndrome","volume":"102","author":"Restivo","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/aur.168","article-title":"Modifying Behavioral Phenotypes in Fmr1ko Mice: Genetic Background Differences Reveal Autistic-Like Responses","volume":"4","author":"Spencer","year":"2011","journal-title":"Autism Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/j.1601-183X.2005.00123.x","article-title":"Altered Anxiety-Related and Social Behaviors in the Fmr1 Knockout Mouse Model of Fragile X Syndrome","volume":"4","author":"Spencer","year":"2005","journal-title":"Genes Brain Behav."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.bbr.2011.04.049","article-title":"Genetic Reduction of Group 1 Metabotropic Glutamate Receptors Alters Select Behaviors in a Mouse Model for Fragile X Syndrome","volume":"223","author":"Thomas","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1111\/j.1601-183X.2012.00784.x","article-title":"Reduction of Bdnf Expression in Fmr1 Knockout Mice Worsens Cognitive Deficits but Improves Hyperactivity and Sensorimotor Deficits","volume":"11","author":"Uutela","year":"2012","journal-title":"Genes Brain Behav."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.bbr.2005.11.004","article-title":"Social Behavior Deficits in the Fmr1 Mutant Mouse","volume":"168","author":"Mineur","year":"2006","journal-title":"Behav. Brain Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1007\/s10803-012-1670-1","article-title":"Brief Report: Altered Social Behavior in Isolation-Reared Fmr1 Knockout Mice","volume":"43","author":"Heitzer","year":"2012","journal-title":"J. Autism Dev. Disord"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Mines, M.A., Yuskaitis, C.J., King, M.K., Beurel, E., and Jope, R.S. (2010). Gsk3 Influences Social Preference and Anxiety-Related Behaviors During Social Interaction in a Mouse Model of Fragile X Syndrome and Autism. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009706"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.neuron.2012.03.009","article-title":"Chronic Pharmacological Mglu5 Inhibition Corrects Fragile X in Adult Mice","volume":"74","author":"Michalon","year":"2012","journal-title":"Neuron"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1097\/00008877-200409000-00018","article-title":"Object Recognition Impairment in Fmr1 Knockout Mice Is Reversed by Amphetamine: Involvement of Dopamine in the Medial Prefrontal Cortex","volume":"15","author":"Ventura","year":"2004","journal-title":"Behav. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S0006-8993(01)03309-1","article-title":"Alterations in the Auditory Startle Response in Fmr1 Targeted Mutant Mouse Models of Fragile X Syndrome","volume":"927","author":"Nielsen","year":"2002","journal-title":"Brain Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbr.2011.11.018","article-title":"Genetic Reduction of Muscarinic M4 Receptor Modulates Analgesic Response and Acoustic Startle Response in a Mouse Model of Fragile X Syndrome (Fxs)","volume":"228","author":"Veeraragavan","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.bbr.2012.01.031","article-title":"Pharmacological Treatment of Fragile X Syndrome with Gabaergic Drugs in a Knockout Mouse Model","volume":"229","author":"Heulens","year":"2012","journal-title":"Behav. Brain Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1196\/annals.1308.002","article-title":"Adolescent Brain Development and Animal Models","volume":"1021","author":"Spear","year":"2004","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/dev.420160203","article-title":"Periadolescence: Age-Dependent Behavior and Psychopharmacological Responsivity in Rats","volume":"16","author":"Spear","year":"1983","journal-title":"Dev. Psychobiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nm.4335","article-title":"Metformin Ameliorates Core Deficits in a Mouse Model of Fragile X Syndrome","volume":"23","author":"Gantois","year":"2017","journal-title":"Nat. Med."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Lemaire-Mayo, V., Piquemal, M., Crusio, W.E., Louette, E., and Pietropaolo, S. (2020). Therapeutic Effects of Chlorzoxazone, a Bkca Channel Agonist, in a Mouse Model of Fragile X Syndrome. bioRxiv, bioRxiv:2020.12.11.389569.","DOI":"10.1101\/2020.12.11.389569"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1007\/s00213-014-3478-5","article-title":"Chronic Cannabidiol Treatment Improves Social and Object Recognition in Double Transgenic Appswe\/Ps1e9 Mice","volume":"231","author":"Cheng","year":"2014","journal-title":"Psychopharmacology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1038\/sj.npp.1301651","article-title":"Wild-Type Male Offspring of Fmr-1+\/\u2212 Mothers Exhibit Characteristics of the Fragile X Phenotype","volume":"33","author":"Zupan","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.bbr.2016.11.051","article-title":"Behavioral Effects of Chronic Stress in the Fmr1 Mouse Model for Fragile X Syndrome","volume":"320","author":"ESubashi","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.psyneuen.2006.02.008","article-title":"Corticosterone Response to Acute Stress in a Mouse Model of Fragile X Syndrome","volume":"31","author":"Markham","year":"2006","journal-title":"Psychoneuroendocrinology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"917183","DOI":"10.3389\/fncel.2022.917183","article-title":"Long-Term Behavioral Effects of Prenatal Stress in the Fmr1-Knock-out Mouse Model for Fragile X Syndrome","volume":"16","author":"Petroni","year":"2022","journal-title":"Front. Cell Neurosci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"7269","DOI":"10.1038\/s41598-022-11083-1","article-title":"Autistic-Like Behavioral Effects of Prenatal Stress in Juvenile Fmr1 Mice: The Relevance of Sex Differences and Gene-Environment Interactions","volume":"12","author":"Petroni","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.neuroscience.2011.06.047","article-title":"Effects of Chronic Immobilization Stress on Anxiety-Like Behavior and Basolateral Amygdala Morphology in Fmr1 Knockout Mice","volume":"194","author":"Qin","year":"2011","journal-title":"Neuroscience"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fnmol.2015.00068","article-title":"Early Life Stress Effects on Glucocorticoid-Bdnf Interplay in the Hippocampus","volume":"8","author":"Daskalakis","year":"2015","journal-title":"Front. Mol. Neurosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S1734-1140(13)71031-4","article-title":"Bdnf and Vegf in the Pathogenesis of Stress-Induced Affective Diseases: An Insight from Experimental Studies","volume":"65","author":"Nowacka","year":"2013","journal-title":"Pharmacol. Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0083-6729(10)82010-2","article-title":"Role of Neurotrophic Factors in Behavioral Processes: Implications for the Treatment of Psychiatric and Neurodegenerative Disorders","volume":"82","author":"Pardon","year":"2010","journal-title":"Vitam. Horm."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3109\/10253890009001124","article-title":"Corticosterone Effects on Bdnf Expression in the Hippocampus. Implications for Memory Formation","volume":"3","author":"Schaaf","year":"2000","journal-title":"Stress"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/0166-4328(95)00220-0","article-title":"Hippocampal Vulnerability to Stress and Aging: Possible Role of Neurotrophic Factors","volume":"78","author":"Smith","year":"1996","journal-title":"Behav. Brain Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.neuroscience.2012.08.065","article-title":"Glucocorticoid Regulation of Brain-Derived Neurotrophic Factor: Relevance to Hippocampal Structural and Functional Plasticity","volume":"239","author":"Suri","year":"2013","journal-title":"Neuroscience"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1385\/JMN:15:2:99","article-title":"Dietary Restriction Increases the Number of Newly Generated Neural Cells, and Induces Bdnf Expression, in the Dentate Gyrus of Rats","volume":"15","author":"Lee","year":"2000","journal-title":"J. Mol. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.pbb.2006.11.021","article-title":"Chronic Mild Stress Inhibits Bdnf Protein Expression and Creb Activation in the Dentate Gyrus but Not in the Hippocampus Proper","volume":"85","author":"Gronli","year":"2006","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1523\/JNEUROSCI.15-03-01768.1995","article-title":"Stress and Glucocorticoids Affect the Expression of Brain-Derived Neurotrophic Factor and Neurotrophin-3 Mrnas in the Hippocampus","volume":"15","author":"Smith","year":"1995","journal-title":"J. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1111\/j.1471-4159.2008.05484.x","article-title":"Long-Lasting Depression-Like Behavior and Epigenetic Changes of Bdnf Gene Expression Induced by Perinatal Exposure to Methylmercury","volume":"106","author":"Onishchenko","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.psyneuen.2007.09.004","article-title":"A Dual Role for Interleukin-1 in Hippocampal-Dependent Memory Processes","volume":"32","author":"Goshen","year":"2007","journal-title":"Psychoneuroendocrinology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nrn2297","article-title":"From Inflammation to Sickness and Depression: When the Immune System Subjugates the Brain","volume":"9","author":"Dantzer","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s11689-017-9184-y","article-title":"Acamprosate in a Mouse Model of Fragile X Syndrome: Modulation of Spontaneous Cortical Activity, Erk1\/2 Activation, Locomotor Behavior, and Anxiety","volume":"9","author":"Schaefer","year":"2017","journal-title":"J. Neurodev. Disord."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.brainres.2011.12.041","article-title":"Minocycline Treatment Reverses Ultrasonic Vocalization Production Deficit in a Mouse Model of Fragile X Syndrome","volume":"1439","author":"Rotschafer","year":"2012","journal-title":"Brain Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"112068","DOI":"10.1016\/j.bbr.2019.112068","article-title":"Reversal of Ultrasonic Vocalization Deficits in a Mouse Model of Fragile X Syndrome with Minocycline Treatment or Genetic Reduction of Mmp-9","volume":"372","author":"Toledo","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_102","first-page":"103","article-title":"Molecular Targets of the Phytocannabinoids: A Complex Picture","volume":"103","author":"Morales","year":"2017","journal-title":"Prog. Chem. Org. Nat. Prod."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"968115","DOI":"10.3389\/fnins.2022.968115","article-title":"Editorial: Targeting Excitation-Inhibition Imbalance in Neurodevelopmental and Autism Spectrum Disorders","volume":"16","author":"Pietropaolo","year":"2022","journal-title":"Front. Neurosci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/15\/1927\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:18:39Z","timestamp":1760127519000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/15\/1927"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,25]]},"references-count":103,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["cells12151927"],"URL":"https:\/\/doi.org\/10.3390\/cells12151927","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,25]]}}}