Abstracts

Rationale: Previous studies have shown that focal temporal lobe seizures with loss of consciousness exhibit increased cortical slow-wave activity with decreased cerebral blood flow (CBF), similar to deep sleep state. Recent work in temporal lobe seizures induced by current injection in the hippocampus of rats has shown growing evidence that decreased activity of subcortical arousal systems cause depressed cortical function during seizures. Activation of GABAergic neurons from the lateral septum and cortical reduction of cholinergic neurotransmission is one possible explanation. While the rat model provides insight for identifying potential networks responsible for impaired consciousness, the poor availability of genetic tools limits the investigation of mechanisms underlying depressed subcortical arousal, e.g. direct inhibition or/and removal of excitation. In addition, behavioral assessment and performance relative to consciousness are impossible to study in this model due to its anesthetized state. Therefore, a mouse model is much more desirable. Here, we present a temporal lobe seizure mouse model with impaired consciousness induced by electrically stimulating hippocampus in an awake, behaving state. Methods: Focal seizures were induced in mice with a 2 s, 60 Hz current injection through a bipolar electrode implanted in the dorsal hippocampus. At the same time, local field potential (LFP) signals were recorded from lateral orbitofrontal cortex (LO). To assess behavioral responses during seizures, mice were water-restricted and trained to lick a spout in responses to sound (0-50 kHz noise, 12 ms) every 10-15 s while head-fixed on a running wheel.  Results: Focal seizures were of 5-20s duration and repeatable for several weeks (n=75 seizures, 7 animals). They were associated with increased slow-wave activity in frontal cortex as observed in patients and rats. Further, licking response to sound was decreased (decreased lick frequency, and increased lick latency, n=7 animals) which recovered post-ictally. Interestingly, response to sound was sometimes normal during seizures suggesting consciousness was not always impaired as seen in patients. Conclusions: We show a new temporal lobe seizure mouse model that shares characteristics seen in both human and rat. The advantages of having control over seizure onset time, the myriad of genetic tools available, combined with the possibility to study behavior concomitantly offer new possibilities to investigate the mechanisms underlying loss of consciousness. Funding: NIH R01 NS066974 and R01 NS096088