{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:46:00Z","timestamp":1792107960604,"version":"4.4.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fragile X syndrome is the most common inherited intellectual disability and mono-genetic cause of autism spectrum disorder. It is a neurodevelopmental condition occurring due to a CGG trinucleotide expansion in the FMR1 gene. Polymorphisms and variants in large-conductance calcium-activated potassium channels are increasingly linked to intellectual disability and loss of FMR protein causes reduced large-conductance calcium-activated potassium channel activity leading to abnormalities in synapse function.<\/jats:p>\n               <jats:p>Using the cannabinoid-like large-conductance calcium-activated potassium channel activator VSN16R we rescued behavioural deficits such as repetitive behaviour, hippocampal dependent tests of daily living, hyperactivity and memory in a mouse model of fragile X syndrome.<\/jats:p>\n               <jats:p>VSN16R has been shown to be safe in a phase 1 study in healthy volunteers and in a phase 2 study in patients with multiple sclerosis with high oral bioavailability and no serious adverse effects reported. VSN16R could therefore be directly utilized in a fragile X syndrome clinical study. Moreover, VSN16R showed no evidence of tolerance, which strongly suggests that chronic VSN16R may have great therapeutic value for fragile X syndrome and autism spectrum disorder.<\/jats:p>\n               <jats:p>This study provides new insight into the pathophysiology of fragile X syndrome and identifies a new pathway for drug intervention for this debilitating disorder.<\/jats:p>","DOI":"10.1093\/brain\/awab246","type":"journal-article","created":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T15:29:09Z","timestamp":1625066949000},"page":"76-82","source":"Crossref","is-referenced-by-count":10,"title":["Reversal of behavioural phenotype by the cannabinoid-like compound VSN16R in fragile X syndrome mice"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8022-9283","authenticated-orcid":false,"given":"Michael J","family":"Hurley","sequence":"first","affiliation":[{"name":"Neuroimmunology, Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO16 6YD, UK"},{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M J","family":"Deacon","sequence":"additional","affiliation":[{"name":"Biomedicine Division, Fraunhofer Research Institute, Center for System Biotechnology, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A W Edith","family":"Chan","sequence":"additional","affiliation":[{"name":"Drug Discovery, UCL Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Baker","sequence":"additional","affiliation":[{"name":"Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London E1 2AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L","family":"Selwood","sequence":"additional","affiliation":[{"name":"Drug Discovery, UCL Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Cogram","sequence":"additional","affiliation":[{"name":"Biomedicine Division, Fraunhofer Research Institute, Center for System Biotechnology, Santiago, Chile"},{"name":"Department of Ecological Sciences, Institute of Ecology and Biodiversity, Faculty of Sciences, Universidad de Chile, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"issue":"4","key":"2022040311205546300_awab246-B1","doi-asserted-by":"crossref","first-page":"190","DOI":"10.25100\/cm.v45i4.1810","article-title":"Fragile X syndrome","volume":"45","author":"Saldarriaga","year":"2014","journal-title":"Colomb Med (Cali)"},{"issue":"2","key":"2022040311205546300_awab246-B2","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1111\/cge.13075","article-title":"Fragile X syndrome: An overview and update of the FMR1 gene","volume":"93","author":"Mila","year":"2018","journal-title":"Clin Genet"},{"issue":"5009","key":"2022040311205546300_awab246-B3","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1126\/science.252.5009.1097","article-title":"Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome","volume":"252","author":"Oberl\u00e9","year":"1991","journal-title":"Science"},{"issue":"5","key":"2022040311205546300_awab246-B4","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"},{"issue":"5009","key":"2022040311205546300_awab246-B5","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1126\/science.252.5009.1179","article-title":"Fragile X genotype characterized by an unstable region of DNA","volume":"252","author":"Yu","year":"1991","journal-title":"Science"},{"key":"2022040311205546300_awab246-B6","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1146\/annurev-pathol-011811-132457","article-title":"Molecular mechanisms of fragile X syndrome: A twenty-year perspective","volume":"7","author":"Santoro","year":"2012","journal-title":"Annu Rev Pathol"},{"issue":"5","key":"2022040311205546300_awab246-B7","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41583-021-00445-9","article-title":"Channelopathies in fragile X syndrome","volume":"22","author":"Deng","year":"2021","journal-title":"Nat Rev Neurosci"},{"issue":"2","key":"2022040311205546300_awab246-B8","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/0896-6273(92)90160-F","article-title":"Calcium-activated potassium channels expressed from cloned complementary DNAs","volume":"9","author":"Adelman","year":"1992","journal-title":"Neuron"},{"issue":"1","key":"2022040311205546300_awab246-B9","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0014-5793(00)01584-2","article-title":"hKCNMB3 and hKCNMB4, cloning and characterization of two members of the large-conductance calcium-activated potassium channel beta subunit family","volume":"474","author":"Behrens","year":"2000","journal-title":"FEBS Lett"},{"issue":"1","key":"2022040311205546300_awab246-B10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/pr.116.012864","article-title":"International Union of Basic and Clinical Pharmacology. C. Nomenclature and properties of calcium-activated and sodium-activated potassium channels","volume":"69","author":"Kaczmarek","year":"2017","journal-title":"Pharmacol Rev"},{"issue":"9","key":"2022040311205546300_awab246-B11","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1176\/ajp.2006.163.9.1622","article-title":"Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation","volume":"163","author":"Laumonnier","year":"2006","journal-title":"Am J Psychiatry"},{"issue":"34","key":"2022040311205546300_awab246-B12","doi-asserted-by":"crossref","first-page":"E4697","DOI":"10.1073\/pnas.1502258112","article-title":"Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome","volume":"112","author":"Tang","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022040311205546300_awab246-B13","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":"H\u00e9bert","year":"2014","journal-title":"Orphanet J Rare Dis"},{"issue":"3","key":"2022040311205546300_awab246-B14","doi-asserted-by":"crossref","first-page":"104","DOI":"10.3390\/ph12030104","article-title":"The cannabinoid-like compound, VSN16R, acts on large conductance, Ca2+-activated K+ channels to modulate hippocampal CA1 pyramidal neuron firing","volume":"12","author":"Tabatabaee","year":"2019","journal-title":"Pharmaceuticals (Basel)"},{"issue":"16","key":"2022040311205546300_awab246-B15","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1111\/bph.13889","article-title":"Big conductance calcium-activated potassium channel openers control spasticity without sedation","volume":"174","author":"Baker","year":"2017","journal-title":"Br J Pharmacol"},{"key":"2022040311205546300_awab246-B16","author":"Farrell","year":"2018"},{"issue":"3","key":"2022040311205546300_awab246-B17","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.nbd.2005.08.019","article-title":"The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo","volume":"21","author":"Mientjes","year":"2006","journal-title":"Neurobiol Dis"},{"issue":"1","key":"2022040311205546300_awab246-B18","doi-asserted-by":"crossref","first-page":"18058","DOI":"10.1038\/s41598-020-74848-6","article-title":"Chronic bryostatin-1 rescues autistic and cognitive phenotypes in the fragile X mice","volume":"10","author":"Cogram","year":"2020","journal-title":"Sci Rep"},{"key":"2022040311205546300_awab246-B19","doi-asserted-by":"crossref","first-page":"e51409","DOI":"10.7554\/eLife.51409","article-title":"Molecular structures of the human Slo1 K+ channel in complex with \u03b24","volume":"8","author":"Tao","year":"2019","journal-title":"Elife"},{"issue":"4","key":"2022040311205546300_awab246-B20","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1073\/pnas.1423094112","article-title":"Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures","volume":"112","author":"Myrick","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"issue":"4","key":"2022040311205546300_awab246-B21","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1177\/153331750201700411","article-title":"Evidence and mechanisms of retrogenesis in Alzheimer's and other dementias: Management and treatment import","volume":"17","author":"Reisberg","year":"2002","journal-title":"Am J Alzheimers Dis Other Demen"},{"issue":"2","key":"2022040311205546300_awab246-B22","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.bbr.2004.05.027","article-title":"Hippocampal lesions, species-typical behaviours and anxiety in mice","volume":"156","author":"Deacon","year":"2005","journal-title":"Behav Brain Res"},{"issue":"8","key":"2022040311205546300_awab246-B23","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1038\/npp.2015.369","article-title":"Targeting translation control with p70 S6 kinase 1 inhibitors to reverse phenotypes in fragile X syndrome mice","volume":"41","author":"Bhattacharya","year":"2016","journal-title":"Neuropsychopharmacology"},{"issue":"2","key":"2022040311205546300_awab246-B24","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.dhjo.2018.11.004","article-title":"Health care for individuals with fragile X Syndrome: Understanding access and quality","volume":"12","author":"Wheeler","year":"2019","journal-title":"Disabil Health J"},{"issue":"2","key":"2022040311205546300_awab246-B25","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/j.1365-2788.2010.01337.x","article-title":"The prevalence and phenomenology of self-injurious and aggressive behaviour in genetic syndromes","volume":"55","author":"Arron","year":"2011","journal-title":"J Intellect Disabil Res"},{"issue":"4","key":"2022040311205546300_awab246-B26","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.neuron.2012.12.018","article-title":"FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels [published correction appears in Neuron. 2013 Apr 10;78(1):205]","volume":"77","author":"Deng","year":"2013","journal-title":"Neuron"},{"key":"2022040311205546300_awab246-B27","doi-asserted-by":"publisher","DOI":"10.1101\/2020.02.12.946780","article-title":"Single cell transcriptomics reveals dysregulated cellular and molecular networks in a fragile X syndrome model","author":"Donnard","journal-title":"bioRxiv"},{"key":"2022040311205546300_awab246-B28","doi-asserted-by":"crossref","first-page":"340","DOI":"10.3389\/fnmol.2017.00340","article-title":"Cell type-specific mRNA dysregulation in hippocampal CA1 pyramidal neurons of the fragile X syndrome mouse model","volume":"10","author":"Ceolin","year":"2017","journal-title":"Front Mol Neurosci"},{"key":"2022040311205546300_awab246-B29","doi-asserted-by":"crossref","first-page":"e46919","DOI":"10.7554\/eLife.46919","article-title":"FMRP has a cell-type-specific role in CA1 pyramidal neurons to regulate autism-related transcripts and circadian memory","volume":"8","author":"Sawicka","year":"2019","journal-title":"Elife"},{"key":"2022040311205546300_awab246-B30","doi-asserted-by":"crossref","first-page":"373","DOI":"10.3389\/fphys.2014.00373","article-title":"BKCa channel dysfunction in neurological diseases","volume":"5","author":"N'Gouemo","year":"2014","journal-title":"Front Physiol"},{"issue":"15","key":"2022040311205546300_awab246-B31","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.2174\/0929867322666150209152712","article-title":"A review on GABA\/glutamate pathway for therapeutic intervention of ASD and ADHD","volume":"22","author":"Purkayastha","year":"2015","journal-title":"Curr Med Chem"},{"issue":"3","key":"2022040311205546300_awab246-B32","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/nrd4555","article-title":"Fragile X disappointments upset autism ambitions","volume":"14","author":"Mullard","year":"2015","journal-title":"Nat Rev Drug Discov"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awab246\/42257444\/awab246.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/145\/1\/76\/43246585\/awab246.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/145\/1\/76\/43246585\/awab246.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,3]],"date-time":"2022-04-03T11:21:16Z","timestamp":1648984876000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/145\/1\/76\/6312552"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,1]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,7,1]]},"published-print":{"date-parts":[[2022,3,29]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awab246","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,1,1]]},"published":{"date-parts":[[2021,7,1]]}}}