Acute Focal Seizures Start As Local Synchronizations of Neuronal Ensembles. uri icon

abstract

  • Understanding seizure formation and spread remains a critical goal of epilepsy research. We used fast in vivo two-photon calcium imaging in male mouse neocortex to reconstruct, with single-cell resolution, the dynamics of acute (4-aminopyridine) focal cortical seizures as they originate within a spatially confined seizure initiation site (intrafocal region), and subsequently propagate into neighboring cortical areas (extrafocal region). We find that seizures originate as local neuronal ensembles within the initiation site. This abnormal hyperactivity engages increasingly larger areas in a saltatory fashion until it breaks into neighboring cortex, where it proceeds smoothly and is then detected electrophysiologically (LFP). Interestingly, PV inhibitory interneurons have spatially heterogeneous activity in intrafocal and extrafocal territories, ruling out a simple role of inhibition in seizure formation and spread. We propose a two-step model for the progression of focal seizures, where neuronal ensembles activate first, generating a microseizure, followed by widespread neural activation in a traveling wave through neighboring cortex during macroseizures.SIGNIFICANCE STATEMENT We have used calcium imaging in mouse sensory cortex in vivo to reconstruct the onset of focal seizures elicited by local injection of the chemoconvulsant 4-aminopyridine. We demonstrate at cellular resolution that acute focal seizures originate as increasingly synchronized local neuronal ensembles. Because of its spatial confinement, this process may at first be undetectable even by nearby LFP electrodes. Further, we establish spatial footprints of local neural subtype activity that correspond to consecutive steps of seizure microprogression. Such footprints could facilitate determining the recording location (e.g., inside/outside an epileptogenic focus) in high-resolution studies, even in the absence of a priori knowledge about where exactly a seizure started.

publication date

  • October 23, 2019