Functional brain imaging in larval zebrafish for characterising the effects of seizurogenic compounds acting via a range of pharmacological mechanisms

Autor:	Piotr Grabowski, Jonathan S. Ball, Joseph Pinion, Andrew D. Randall, Jeremy Metz, Will S. Redfern, Malcolm J. Hetheridge, Marc Goodfellow, Matthew J. Winter, Charles R. Tyler, Karen Tse, Aya Takesono, Anna Tochwin, Maciej Trznadel
Rok vydání:	2021
Předmět:	0301 basic medicine Pharmacology biology Drug discovery Functional Neuroimaging Brain medicine.disease biology.organism_classification Reuptake 03 medical and health sciences Epilepsy 030104 developmental biology 0302 clinical medicine Seizures Functional neuroimaging Larva Monoaminergic medicine Animals Cholinergic Neuroscience Zebrafish 030217 neurology & neurosurgery Neuropharmacology
Zdroj:	British Journal of Pharmacology. 178:2671-2689
ISSN:	1476-5381 0007-1188
DOI:	10.1111/bph.15458
Popis:	BACKGROUND AND PURPOSE Functional brain imaging using genetically encoded Ca2+ 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 GABAA 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-induced seizures and testing antiepileptic drug efficacy. EXPERIMENTAL APPROACH Using light-sheet imaging, we systematically analysed the responsiveness of 4 days 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. KEY RESULTS 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-specific circuitry in the larval zebrafish brain. Many seizure-associated compounds also exhibited altered whole brain functional connectivity compared with controls. CONCLUSIONS AND IMPLICATIONS 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-scale pharmacological activation of local circuits, to the large network-wide abnormal synchronous activity associated with seizures.
Databáze:	OpenAIRE
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