All-optical interrogation of excitability during seizure propagation reveals high local inhibition amidst baseline excitability

Abstract

Seizures are classically described as an epiphenomenon of hyperexcitability and hypersynchronicity across brain regions. However, this view is insufficient to explain the complex, dynamic evolution of focal-onset seizures in the brain. Recent studies have proposed mechanisms involving an evolution of excitability driven specifically by a spatiotemporally progressing seizure wavefront. These mechanisms attempt to align the abnormal propagation of neural activity with well-known neurobiological parameters, such as excitation-inhibition balance and neuronal connectivity patterns. We describe a direct test of these mechanisms by performing real-time, in vivo investigations of excitability in the acutely epileptic state and during seizure propagation. We used all-optical interrogation to test single-neuronal and local-circuit excitability in the epileptic brain. We demonstrate a surprising paradox during the acutely epileptic state, wherein the brain becomes susceptible to large synchronous inputs, yet single-cell excitability is largely maintained at baseline levels. At a finer scale, excitability of neurons at the single-cell level is related to their distance from the seizure wavefront. Local circuit excitability is increased in the distal penumbra but, crucially, we find inhibition in close proximity to the seizure wavefront. This is in contrast with previously suggested notions of widespread inhibition outside the direct area of action during a focal-onset seizure. These experimental results provide the first direct, in vivo evidence for the precise spatial scale over which single-cell excitability dynamics evolve during seizure propagation, providing support for local inhibitory restraint of seizure propagation.