Up and Down States of Cortical Neurons in Focal Limbic Seizures

Abstract

Recent work suggests an important role for cortical–subcortical networks in seizure-related loss of consciousness. Temporal lobe seizures disrupt subcortical arousal systems, which may lead to depressed cortical function and loss of consciousness. Extracellular recordings show ictal neocortical slow waves at about 1 Hz, but it is not known whether these simply represent seizure propagation or alternatively deep sleep-like activity, which should include cortical neuronal Up and Down states. In this study, using in vivo whole-cell recordings in a rat model of focal limbic seizures, we directly examine the electrophysiological properties of cortical neurons during seizures and deep anesthesia. We found that during seizures, the membrane potential of frontal cortical secondary motor cortex layer 5 neurons fluctuates between Up and Down states, with decreased input resistance and increased firing rate in Up states when compared to Down states. Importantly, Up and Down states in seizures are not significantly different from those in deep anesthesia, in terms of membrane potential, oscillation frequency, firing rate, and input resistance. By demonstrating these fundamental similarities in cortical electrophysiology between deep anesthesia and seizures, our results support the idea that a state of decreased cortical arousal may contribute to mechanisms of loss of consciousness during seizures.

Arousal and Consciousness in Focal Seizures

“…Cortical neuronal recordings showed Up and Down states of action potential firing and membrane potential oscillations mimicking the physiology of deep sleep and anesthesia. [13][14][15][16]19,20 Why is cortical arousal depressed during focal limbic seizures? Human data showed altered activity in subcortical arousal areas such as the upper brainstem and thalamus (Figure 1B), leading to the network inhibition hypothesis.…”

Cortical low‐frequency power correlates with behavioral impairment in animal model of focal limbic seizures

“…Characteristics of focal limbic seizures, the type that most commonly affects consciousness, include (1) variable impairment in behavior, 9 (2) high‐amplitude delta oscillations in association cortices, 10 and (3) hemodynamic increases in upper brain stem/medial thalamus and decreases in association cortices 11 . The "network inhibition" hypothesis, 12 supported by evidence from our animal model work, 13,14 proposes that focal limbic seizures impair level of consciousness by inhibiting subcortical arousal systems, resulting in low‐frequency cortical oscillations 14–19 . However, our prior studies dissecting these mechanisms were performed under light anesthesia, which can affect electrophysiology and limit behavioral study.…”

The Molecular Genetic Interaction Between Circadian Rhythms and Susceptibility to Seizures and Epilepsy

“…At the cellular level, these oscillations are characterized by depolarized "Up" states and hyperpolarized "Down" states, with neurons in the Up state having increased firing rate and decreased input resistance. A few studies suggest that these states are also present in epileptic seizures that occur both in humans (38) and rodents (39), which is interesting, given that many seizure types also inhibit consciousness. One study using in vivo whole-cell recordings in a rat model of focal limbic seizures found that the membrane potential of frontal cortical secondary motor cortex layer 5 neurons oscillated during seizures and produced Up and Down states comparable to those seen during anesthesia (39).…”

“…A few studies suggest that these states are also present in epileptic seizures that occur both in humans (38) and rodents (39), which is interesting, given that many seizure types also inhibit consciousness. One study using in vivo whole-cell recordings in a rat model of focal limbic seizures found that the membrane potential of frontal cortical secondary motor cortex layer 5 neurons oscillated during seizures and produced Up and Down states comparable to those seen during anesthesia (39). Taken together, these findings shed light on mechanisms potentially linking sleep with certain types of seizures in epilepsy.…”