Abstracts

Rationale: Temporal lobe epilepsy is characterized by focal seizures originating from limbic systems and concomitant deficits in consciousness, which often have serious negative consequences such as motor vehicle accidents, decreased school and work performance and social stigmatization. Approaches to restoring patients’ consciousness during temporal lobe seizures could be beneficial to significantly improve their quality of life. In order to achieve this aim, it is imperative first to understand the physiological and neuroanatomical basis of ictal unconsciousness._x000D_
Previous studies in our lab have identified the inhibition of the brainstem and basal forebrain cholinergic neurons as potential drivers of depressed arousal during temporal lobe seizures. However, these conclusions were demonstrated in “light-anesthesia” rats, which thus need to be verified in our new awake, behaving mouse model. Furthermore, using an awake mouse model allows exploration of changes in pupil diameter and animal behavior to evaluate the loss of consciousness in temporal lobe seizures.

Methods: Mice were head-fixed on a running wheel. Local field potentials were measured with chronically implanted bipolar electrodes in the right lateral orbitofrontal cortex and bilateral hippocampi. Induction of focal limbic seizures was accomplished by the application of current pulses (2 s, 60 Hz) into the hippocampus. We used tungsten microelectrode for multi-unit activity (MUA) recording and glass capillaries filled with 4% Neurobiotin for juxtacellular single unit activity (SUA) recordings. Cholinergic neurons in the nucleus basalis of Meynert were identified by staining with anti-choline acetyltransferase antibodies.

Results: MUA recordings showed an overall decrease in neuronal firing frequency in the nucleus basalis of Meynert during periods of focal hippocampal seizures. Running wheel behavior was also depressed during seizures and orbital frontal local field potentials showed slow wave activity, similar to human patients with temporal lobe epilepsy. SUA recordings were also successfully accomplished from neurons in the nucleus basalis of Meynert and neurons were identified by immunohistochemistry.

Conclusions: These early results suggest that stable multi-unit and juxtacellular single unit recording of neurons in the deep subcortical areas are possible in awake, moving mice during seizures. Additionally, the inhibition of neurons in the nucleus basalis of Meynert appears to play a potential role in the modulation of arousal during focal limbic seizures. Further investigation of specific subcortical neurons and neurotransmitters affected during seizures is vital in uncovering the mechanisms underlying ictal unconsciousness and may bring about promising treatments for people suffering from epilepsy.

Funding: NIH R01 NS066974