A novel mouse model of focal limbic seizures that reproduces behavioral impairment associated with cortical slow wave activity

Abstract

Patients with focal temporal lobe seizures often experience loss of consciousness. In humans, this loss of consciousness has been shown to be positively correlated with EEG neocortical slow waves, similar to those seen in non-REM sleep. Previous work in rat models of temporal lobe seizures suggests that decreased activity of subcortical arousal systems cause depressed cortical function during seizures. However, these studies were performed under light anesthesia, making it impossible to correlate behavior, and therefore consciousness, to electrophysiologic data. Further, the genetic and molecular toolkits allowing for precise study of the underlying neural circuitry are much more developed in mice than in rats. Here, we describe an awake-behaving, head-fixed mouse model of temporal lobe seizures with both spared and impaired behavior reflecting level of consciousness. Water-restricted mice were head-fixed on a running wheel and trained to associate an auditory stimulus to the delivery of a drop of water from a dispenser. To investigate the effect of seizures on behavior, seizures were electrically induced by stimulating either the left or right hippocampus via a chronically-implanted electrode, while mice were performing the task. Behavior was measured by monitoring lick responses to the auditory stimulus and running speed on the wheel. Further, local field potentials (LFP) signals were simultaneously recorded from hippocampus and orbitofrontal cortex (OFC). Induced focal seizures were 5-30s in duration, and repeatable for several weeks (n=20 animals). Behavioral responses showed a decrease in lick rate to auditory stimulus, and decreased running speed during seizures (p<0.01, n=20 animals). Interestingly, licking response to sound could vary from being impaired to normal during seizures. We found that behavioral impairment is correlated with large amplitude cortical slow-wave activity in frontal cortex, as seen in patients with temporal lobe seizures. These results suggest that induced focal limbic seizures in the mouse can impair consciousness and that the impaired consciousness is correlated with depressed cortical function resembling slow wave sleep. This novel mouse model has similar characteristics with previously studied rat models and human temporal lobe seizures. By leveraging the genetic and molecular techniques available in the mouse, this model can be used to further uncover fundamental mechanisms for loss of consciousness in focal seizures.