Rationale:
Temporal lobe epilepsy (TLE) is a neurological disorder characterized by recurrent seizures that occur in the temporal lobe. One of the symptoms experienced by TLE patients is impaired consciousness. Previous studies have shown that decreased subcortical arousal may be responsible for this symptom. However, the underlying mechanisms are not fully understood.
Recent investigations in an anesthetized rat model suggest that the lateral septum (LS) may play a crucial role in inhibiting subcortical arousal during focal limbic seizures. The LS is composed of predominantly GABAergic neurons and connects the hippocampus with the subcortical arousal systems. Previous studies have shown that focal hippocampal seizures in rats induce increased neuronal activity and blood flow in the LS. Additionally, stimulation of the LS without seizures resulted in cortical slow oscillations.
Based on these findings, we hypothesize that the hyper-excitatory hippocampal state during seizures propagates to the LS, which increases GABAergic inhibition from LS to subcortical arousal systems leading to neocortical deactivation indirectly.
Methods:
To investigate this hypothesis, an awake-behaving mouse model was used, where focal limbic seizures were induced by stimulating the hippocampus. Local field potential (LFP) signals were recorded from the hippocampus, with simultaneous LFP 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 knock-in mice. Mouse running wheel behavior was also recorded.
Results:
The results showed that impaired consciousness was present during focal limbic seizures, measured by decreased running wheel speed (n=9). This was associated with slow wave activity in the OFC (n=9), increased LS neuronal MUA firing (n=9), and GABAergic neuronal-specific Calcium indicator fluorescent intensity increases during seizures (n=5). These findings demonstrate a direct correlation between neocortical deactivation, behavioral arrest, and increased activity in LS GABAergic neurons in the presence of a hyper-excitatory hippocampal state in a temporal lobe seizure model.
Conclusions:
The results of this study suggest that the lateral septum (LS) plays a crucial role in mediating impaired consciousness during focal limbic seizures. The hyper-excitatory hippocampal state during seizures propagates to the LS, which increases GABAergic inhibition from LS to subcortical arousal systems leading to neocortical deactivation indirectly. Further investigation into network and neurotransmitter mechanisms, such as the measurement of neurotransmitters in downstream subcortical arousal areas influenced by LS including the nucleus basalis, may lead to novel treatments for this disorder.
Funding: NIH R01 NS066974