Cellular resolution contributions to ictal population signals.

Area of Science:

• Neuroscience
• Epilepsy Research
• Cellular Electrophysiology

Background:

• Increased ictal activity amplitude is a hallmark of epileptic seizures.
• Current clinical methods measure population-level electrographic signals, limiting understanding of individual neuronal contributions.
• Potential sources of increased population signal include neuronal synchrony, altered active states, and altered subthreshold states.

Purpose of the Study:

• To quantify the cellular determinants contributing to the amplitude of ictal activity.
• To differentiate the roles of neuronal synchrony, active states, and subthreshold states in seizure signal generation.
• To link single-neuron activity to population-level seizure measures.

Main Methods:

• Simultaneous GCaMP-based calcium imaging and whole-cell patch-clamp recordings in organotypic hippocampal slice cultures (OHSCs).
• Microendoscopy in APP/PS1 mice with focal cortical injury to assess spontaneous seizure activity.
• Widefield imaging in OHSCs to model posttraumatic epilepsy.
• Neuronal resolution calcium imaging to quantify cellular contributions to population signals.

Main Results:

• Seizure onset signal is primarily driven by increased subthreshold neuronal activity (e.g., excitatory postsynaptic potentials, membrane depolarization).
• Neuronal recruitment into the active state increases as seizures progress.
• The increasing fraction of active cells is mainly due to synchronous reactivation, not new neuronal recruitment.

Conclusions:

• This study establishes a critical link between single neuron activity and population measures of seizure activity.
• Understanding these cellular determinants can inform future therapeutic strategies for epilepsy.