Whole brain seizure networks in zebrafish models of GABRA1 and GABRG2 related epilepsies

R. E. Rosch^{1,2,3 }, D. R. W. Burrows^{1 }, É. Samarut⁴, M. P. Meyer¹

1 - MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; 2 - Complex Systems Group, Department of Bioengineering, University of Pennsylvania, Philadelphia PA, USA; 3 - Department of Paediatric Neurology, Great Ormond Street Hospital NHS Foundation Trust, London, UK; 4 - Department of Neurosciences, Research Centre of the University of Montreal Hospital Center, Montreal QC, Canada;

* These authors contributed equally

Knock-outs of gabra1 and gabrg2 cause epileptic phenotypes in zebrafish

GABA-A receptors are the predominant fast inhibitory neurotransmitters in the brain and are implicated in epilepsy
Zebrafish have emerged as novel a novel model organism for epilepsy research, with an increasing number of genetic lines now in development
Zebrafish lines of two human genetic epilepsies GABRA1 and GABRG2 show evidence of reflex convulsive seizures
Loss of function in different GABA-A subunits is associated with behaviourally distinct phenotypes in zebrafish models of the disorder

There are persistent genotype-specific functional brain network differences

We estimate time varying interregional functional connectivity over a five minute time window following light stimulation
After initial response to the light stimulation, functional connectivity reaches a steady state
The steady state is dominated by distinct, genotype specific steady state connectivity patterns
The different KO zebrafish lines show distinct differences in functional connectivity, extending beyond ictal stimulus responses

Neuronal responses to visual stimuli show genotype-specific signatures

We performed light sheet imaging of 3-4 PTU-raised wildtype, gabra1 -/-, and gabrg2 -/- larvae at 6-8dpf
Both gabra1 -/-, and gabrg2 -/- larvae show patterns of hyuperexcitability in response to light stimulation
The predominant different in overall activity distribution occurs early after light exposure
Brain-wide light-induced responses in the different lines are separable in even a low dimensional representation

GABA subunit knockouts affect distinct parts of synaptic network coupling

distributed difference in functional connectivity may result from more localised differences in effective connectivity
dynamic causal modelling (DCM) allows us to estimate parameters of a biophysical population model based on the observed data
we find genotype specific differences in network connectivity of these model descriptions
GABA subunit knockouts may target anatomically or physiologically defined subsets of GABAergic synapses