Abstracts

Rationale: In humans, focal temporal lobe seizures with loss of consciousness are positively correlated with neocortical slow waves on EEG, similar to the non-REM sleep state. Previous work in a rat model of focal limbic seizures suggests a key role for inhibition of subcortical arousal systems, including brainstem and basal forebrain cholinergic neurons. However, a mouse model is much more desirable due to the wealth of genetics tools available for investigation of specific cellular and network mechanisms. Methods: Water-restricted mice were trained to lick a spout in response to a sound (0-50kHz noise, 12ms) every 10-15s while head-fixed on a running wheel. Seizure initiation and cortical recordings were performed via implanted bipolar electrodes in the dorsal hippocampus (LFP recording and stimulating) and into the right orbitofrontal cortex (OFC) (LFP recording). Focal limbic seizures were induced by a 2s, 60 Hz hippocampal stimulus. Multiunit activity (MUA) recordings in left OFC were performed via a tungsten electrode. Results: Focal seizures were of 5-30s duration and repeatable for several weeks (n=15 animals). Licking responses to sound, as well as running speed, was decreased during seizures and recovered post-ictally (p<0.01, n=15 animals). Interestingly, response to sound was sometimes normal during seizures. By examining cortical activity and behavioral responses, we showed that behavioral arrest is correlated with amplitude of cortical slow-wave activity, as seen in humans with temporal lobe seizures. Furthermore, the cortical slow waves followed an Up and Down state firing pattern on MUA recordings, similar to the slow wave sleep state (n=2 animals). Conclusions: This novel mouse model of focal limbic seizures shares characteristics with the rat model and with temporal lobe seizures in humans. These results suggest impaired consciousness can occur during induced focal limbic seizures in the mouse, and that this impairment is associated with depressed cortical function resembling slow wave sleep. Future work with this model may be beneficial to uncover the fundamental mechanisms for loss of consciousness in focal seizures, leading to innovative treatment approaches for this common disorder. Funding: NIH R01 NS066974 and R01 NS096088