Abstracts

Rationale: Temporal lobe epilepsy (TLE) is a neurological disorder characterized by recurrent seizures that occur in the temporal lobe. TLE patients often experience impaired consciousness. Previous studies have shown that decreased subcortical arousal may be responsible for this symptom. However, the underlying mechanisms are not fully understood.

Investigations in rats suggest that the lateral septum (LS) may play a crucial role in inhibiting subcortical arousal during focal seizures. Previous studies have shown that focal seizures in rats induce increased neuronal activity and blood flow in the LS. Stimulation of the LS without seizures resulted in cortical slow waves and impaired behavioral responsiveness. Rat anatomical tracer studies showed direct projections of LS neurons to the nucleus basalis (NB) and indirect projections via the thalamic paratenial nucleus (PT).

We hypothesize that the hyper-excitatory hippocampal state during focal seizures with impaired consciousness propagates to the LS, which increases GABAergic inhibition from LS to subcortical arousal systems leading to neocortical deactivation via direct inhibition and indirect de-excitation.


Methods: An awake mouse model was used, where focal seizures were induced by electrically stimulating the hippocampus. Local field potentials (LFPs) were recorded from the hippocampus, with simultaneous LFPs from the orbitofrontal cortex (OFC) and multiunit activity (MUA) recordings from the LS. Cell-specific (GABAergic neuron) recording through fiber photometry in the LS was accomplished using a genetically encoded calcium indicator (GCaMP) in combination with Gad2-IRES-Cre mice. GABA and Glutamate (Glu) sensing was performed in the NB separately. Mouse running wheel behavior was recorded.

Results: The results showed that impaired consciousness marked by decreased running speed (n=9) was associated with a significant increase in slow wave activity in the OFC (n=9) during focal seizures. Significantly increased LS neuronal MUA firing (n=10) and GABAergic neuronal-specific calcium indicator fluorescent intensity (n=10) were recorded during focal seizures with impaired consciousness.

GABA level in the NB increased significantly (n=7) during focal seizures with impaired consciousness, and this increase continued in the postictal period. Glu level decreased significantly (n=8) during focal seizures with impaired consciousness and began to increase in the postictal period.


Conclusions: These findings demonstrate a direct relationship between neocortical deactivation, behavioral arrest, and increased activity in LS GABAergic neurons during focal seizures with impaired consciousness.

The NB GABA/Glu measures demonstrated increased GABAergic inhibition from LS to subcortical arousal systems via parallel pathways, i.e., direct inhibition (increased GABA release) and indirect de-excitation (decreased Glu release). The postictal findings suggest that persistently depressed arousal in subcortical networks may play an important role in postictal impaired consciousness following focal seizures. Further investigation into network and neurotransmitter mechanisms may lead to novel treatments.


Funding: R01 NS066974