Seizures initiate in zones of relative hyperexcitation in a zebrafish epilepsy model

Abstract

Abstract Seizures are thought to arise from an imbalance of excitatory and inhibitory neuronal activity. While most classical studies suggest excessive excitatory neural activity plays a generative role, some recent findings challenge this view and instead argue that excessive activity in inhibitory neurons initiates seizures. We investigated this question of imbalance in a zebrafish seizure model with multi-regional two-photon imaging of excitatory and inhibitory neuronal activity using a nuclear-localized calcium sensor. We found that seizures consistently initiated in circumscribed zones of the midbrain before propagating to other brain regions. Excitatory neurons were both more prevalent and more likely to be recruited than inhibitory neurons in initiation as compared with propagation zones. These findings support a mechanistic picture whereby seizures initiate in a region of hyper-excitation, then propagate more broadly once inhibitory restraint in the surround is overcome. Teaser We uncover the roles of excitation and inhibition during seizures, thus opening a path to more targeted therapy of epilepsy.