{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:15:37Z","timestamp":1792649737510,"version":"4.5.0"},"reference-count":68,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T00:00:00Z","timestamp":1620172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/L020637\/1"],"award-info":[{"award-number":["BB\/L020637\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/P025528\/1"],"award-info":[{"award-number":["BB\/P025528\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010757","name":"National Centre for the Replacement Refinement and Reduction of Animals in Research","doi-asserted-by":"publisher","award":["NC\/R001421\/1"],"award-info":[{"award-number":["NC\/R001421\/1"]}],"id":[{"id":"10.13039\/501100010757","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000737","name":"University of Exeter","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000737","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Functional brain imaging using genetically encoded Ca<jats:sup>2+<\/jats:sup> sensors in larval zebrafish is being developed for studying seizures and epilepsy as a more ethical alternative to rodent models. Despite this, few data have been generated on pharmacological mechanisms of action other than GABA<jats:sub>A<\/jats:sub> antagonism. Assessing larval responsiveness across multiple mechanisms is vital to test the translational power of this approach, as well as assessing its validity for detecting unwanted drug\u2010induced seizures and testing antiepileptic drug efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Using light\u2010sheet imaging, we systematically analysed the responsiveness of 4\u00a0days post fertilisation (dpf; which are not considered protected under European animal experiment legislation) transgenic larval zebrafish to treatment with 57 compounds spanning more than 12 drug classes with a link to seizure generation in mammals, alongside eight compounds with no such link.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We show 4dpf zebrafish are responsive to a wide range of mechanisms implicated in seizure generation, with cerebellar circuitry activated regardless of the initiating pharmacology. Analysis of functional connectivity revealed compounds targeting cholinergic and monoaminergic reuptake, in particular, showed phenotypic consistency broadly mapping onto what is known about neurotransmitter\u2010specific circuitry in the larval zebrafish brain. Many seizure\u2010associated compounds also exhibited altered whole brain functional connectivity compared with controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>This work represents a significant step forward in understanding the translational power of 4dpf larval zebrafish for use in neuropharmacological studies and for studying the events driving transition from small\u2010scale pharmacological activation of local circuits, to the large network\u2010wide abnormal synchronous activity associated with seizures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15458","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T08:51:32Z","timestamp":1616748692000},"page":"2671-2689","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Functional brain imaging in larval zebrafish for characterising the effects of seizurogenic compounds acting via a range of pharmacological mechanisms"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3668-6564","authenticated-orcid":false,"given":"Matthew J.","family":"Winter","sequence":"first","affiliation":[{"name":"Biosciences, College of Life and Environmental Sciences University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Pinion","sequence":"additional","affiliation":[{"name":"Biosciences, College of Life and Environmental Sciences University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Tochwin","sequence":"additional","affiliation":[{"name":"Biosciences, College of Life and Environmental Sciences University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Takesono","sequence":"additional","affiliation":[{"name":"Biosciences, College of Life and Environmental Sciences University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan S.","family":"Ball","sequence":"additional","affiliation":[{"name":"Biosciences, College of Life and Environmental Sciences University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Grabowski","sequence":"additional","affiliation":[{"name":"Data Science and Artificial Intelligence, Clinical Pharmacology &amp; Safety Sciences AstraZeneca R&amp;D  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Metz","sequence":"additional","affiliation":[{"name":"Biosciences, College of Life and Environmental Sciences University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Trznadel","sequence":"additional","affiliation":[{"name":"Biosciences, College of Life and Environmental Sciences University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Tse","sequence":"additional","affiliation":[{"name":"Safety &amp; Mechanistic Pharmacology, Clinical Pharmacology &amp; Safety Sciences AstraZeneca R&amp;D  Cambridge UK"},{"name":"Sovereign House GW Pharmaceuticals plc  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7767-9515","authenticated-orcid":false,"given":"Will S.","family":"Redfern","sequence":"additional","affiliation":[{"name":"Safety &amp; Mechanistic Pharmacology, Clinical Pharmacology &amp; Safety Sciences AstraZeneca R&amp;D  Cambridge UK"},{"name":"Simcyp Division Certara UK Limited  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm J.","family":"Hetheridge","sequence":"additional","affiliation":[{"name":"Biosciences, College of Life and Environmental Sciences University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Goodfellow","sequence":"additional","affiliation":[{"name":"Department of Mathematics &amp; Living Systems Institute and EPSRC Centre for Predictive Modelling in Healthcare University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Randall","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles R.","family":"Tyler","sequence":"additional","affiliation":[{"name":"Biosciences, College of Life and Environmental Sciences University of Exeter  Exeter Devon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11057"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14748"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14752"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14753"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14749"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/bjaceaccp\/mkh002"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2005.03.006"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuro.2019.12.001"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2004.11.031"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2008.05.130"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2008.0213"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.11.024"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2020.01.006"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.9b00335"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14153"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00327.2011"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntt.2017.04.002"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11739-z"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2009.06.003"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/096032718700600314"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.09.060"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2007.09.016"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-53497-2.00017-6"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10541-1"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2013.00053"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201100120"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/609428"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2012.239590"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12127"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.2147\/NDT.S50371"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfw156"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2011.12.043"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0262-8856(92)90076-F"},{"issue":"2","key":"e_1_2_12_35_1","first-page":"24","article-title":"A brief review of the pharmacology of amitriptyline and clinical outcomes in treating fibromyalgia","volume":"5","author":"Lawson K.","year":"2017","journal-title":"Biomedicine"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15178"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07289-5"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0041-19.2019"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000539-200105000-00043"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1089\/zeb.2010.0669"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.10.017"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-23906-1"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2507"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3581"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14105"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/718591"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1006375"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00082"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1586\/14737175.6.4.575"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.10.026"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-007-0053-z"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(88)90235-X"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/0091-3057(88)90482-0"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3947"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2011.00002"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1171"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3940-12.2013"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03087-z"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2010.03.008"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.453"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2017.11.003"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0049-20.2020"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3040"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.10.024"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2008.01.004"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-06646-6"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16067"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1019-12.2012"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-017-9855-1"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.15458","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.15458","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.15458","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T18:20:45Z","timestamp":1693333245000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.15458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,5]]},"references-count":68,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["10.1111\/bph.15458"],"URL":"https:\/\/doi.org\/10.1111\/bph.15458","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,5]]},"assertion":[{"value":"2020-10-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}