In vivo Calcium Imaging Reveals Disordered Interictal Network Dynamics in Epileptic <i>stxbp1b</i> Zebrafish

Abstract

Mutations in STXBP1, encoding a presynaptic protein MUNC18-1, are associated with encephalopathy, developmental delay, intellectual disability and epilepsy. While neural networks are known to operate at a critical state in a healthy brain, network behavior during pathological epileptic states remains unclear. Examining activity in an epileptic brain, during periods between well-characterized hyper-synchronized ictal seizure events (i.e., interictal period), could provide a valuable step towards our overall understanding of networks that participate in generation of epileptic seizures. To study these networks in the context of STXBP1 mutations, we combine a larval zebrafish model of epilepsy with in vivo fast confocal calcium imaging and extracellular local field potential recordings to map network dynamics during interictal periods. We show that stxbp1b mutant larvae display transient periods of elevated activity among local clusters of interacting neurons. These events, termed network “cascades” were significantly larger in size and duration in mutant larvae. At meso-scale resolution, cascades exhibit neurodevelopmental abnormalities in stxbp1b mutants and were sensitive to gap junction blockers. We also describe spontaneous hyper-synchronized neuronal ensembles at single-cell scale in these mutants. Our observation that fast calcium imaging can reveal a uniquely disordered brain state during periods between pathological seizure events is striking and represents a potential interictal biomarker.