Cortical Up State Activity Is Enhanced After Seizures: A Quantitative Analysis

Abstract

In the neocortex, neurons participate in epochs of elevated activity, or Up states, during periods of quiescent wakefulness, slow-wave sleep, and general anesthesia. The regulation of firing during and between Up states is of great interest because it can reflect the underlying connectivity and excitability of neurons within the network. Automated analysis of the onset and characteristics of Up state firing across different experiments and conditions requires a robust and accurate method for Up state detection. Using measurements of membrane potential mean and variance calculated from whole-cell recordings of neurons from control and postseizure tissue, the authors have developed such a method. This quantitative and automated method is independent of cell- or condition-dependent variability in underlying noise or tonic firing activity. Using this approach, the authors show that Up state frequency and firing rates are significantly increased in layer 2/3 neocortical neurons 24 hours after chemo-convulsant-induced seizure. Down states in postseizure tissue show greater membrane-potential variance characterized by increased synaptic activity. Previously, the authors have found that postseizure increase in excitability is linked to a gain-of-function in BK channels, and blocking BK channels in vitro and in vivo can decrease excitability and eliminate seizures. Thus, the authors also assessed the effect of BK-channel antagonists on Up state properties in control and postseizure neurons. These data establish a robust and broadly applicable algorithm for Up state detection and analysis, provide a quantitative description of how prior seizures increase spontaneous firing activity in cortical networks, and show how BK-channel antagonists reduce this abnormal activity.

Abnormal UP/DOWN Membrane Potential Dynamics Coupled with the Neocortical Slow Oscillation in Dentate Granule Cells during the Latent Phase of Temporal Lobe Epilepsy

“…The only study on the consequences of a status epilepticus on intracellular UP/DOWN state V m dynamics was performed in vitro using neocortical slices ( Gerkin et al, 2010 ). In that work, the frequency of UP states recorded in layer 2/3 neocortical pyramidal neurons was increased 24 h after a picrotoxin-induced seizure.…”

Power Laws from Linear Neuronal Cable Theory: Power Spectral Densities of the Soma Potential, Soma Membrane Current and Single-Neuron Contribution to the EEG

“…If future experiments indeed confirm that the BK channel is a dominant source of membrane noise, this may have direct implication of the understanding several pathologies. Not only has the BK channel been implicated as a source of increased neural excitability [54] and epilepsy [55], but also disorders such as schizophrenia [56], autism and mental retardation [57] have been linked to the BK channel through a decrease in its expression [58].…”

Increased presynaptic excitability in a migraine with aura mutation

“…We wanted to test whether the cellular and synaptic phenotypes we observed in vitro , were reflected in sensory network phenotypes in vivo. Cortical slow oscillations (1Hz), expressed as depolarized ‘up state’ and hyperpolarized ‘down states’, represent a form of dynamic gain modulation 34,35 . The depolarized ‘up states’ increase the likelihood of neuronal AP generation upon feedforward stimulus 35–37 .…”

“…Cortical slow oscillations (1Hz), expressed as depolarized ‘up state’ and hyperpolarized ‘down states’, represent a form of dynamic gain modulation 34,35 . The depolarized ‘up states’ increase the likelihood of neuronal AP generation upon feedforward stimulus 35–37 . We recorded membrane responses of S1 L2/3 pyramidal neurons to network driven up and down states using in vivo current clamp recordings.…”

“…Increased ‘up state’ frequency and duration are often regarded as markers for network excitability - e.g. in epilepsy 35,36 . Like epilepsy patients, migraine patients show alterations in both high- and low-frequency cortical and thalamocortical oscillations; the latter are likely correlates of upstates 44,76 .…”