In vivo imaging of seizure activity in a novel developmental seizure model

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Abstract

The immature brain is exceptionally susceptible to seizures. However, it remains unclear whether seizures occurring during development affect critical processes underlying neural circuit formation, leading to long-term functional consequences. Here we characterize a novel in vivo model system of developmental seizures based on the transparent albino Xenopus laevis tadpole, which allows direct examination of seizure activity, and seizure-induced effects on neuronal development within the intact unanesthetized brain. Pentylenetetrazol (PTZ), kainic acid, bicuculline, picrotoxin, 4-aminopyridine, and pilocarpine were tested for their ability to induce behavioral seizures in freely swimming tadpoles when bath applied. All six chemoconvulsants consistently induced similar patterns of abnormal behavior in a dose-dependent manner, characterized by convulsive clonus-like motor patterns with periods of behavioral arrest. Extracellular field recordings demonstrated rhythmic synchronous epileptiform electrographic responses induced by convulsants irrespective of mechanism of action, that could be terminated by the anti-epileptic drug valproate. PTZ-induced seizures were further characterized using in vivo two-photon fluorescence imaging of neuronal calcium dynamics, in unanesthetized immobilized tadpoles. Imaging of calcium dynamics during PTZ-induced seizures revealed waves of neural activity propagating through large populations of neurons within the brain. Analysis of single-cell responses demonstrated distinct synchronized high-amplitude calcium spikes not observed under baseline conditions. Similar to other developmental seizure models, prolonged seizures failed to induce marked neuronal death within the brain, detected by cellular propidium iodide incorporation in vivo or TUNEL labeling. This novel developmental seizure model system has distinct advantages for controlled seizure induction, and direct visualization of both seizure activity and seizure-induced effects on individual developing neurons within the intact unanesthetized brain. Such a system is necessary to address important questions relating to the long-term impact of common perinatal seizures on developing neural circuits.

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