A Hippocampal-Entorhinal Cortex Neuronal Network for Dynamical Mechanisms of Epileptic Seizure

Temporal lobe epilepsy (TLE) is thought to be associated with neuronal hyperexcitability in the hippocampal-entorhinal cortical (EC) circuit. Due to the complexity of the hippocampal-EC network connections, the biophysical mechanisms of the different circuits in epilepsy generation and propagation are still not fully established. In this work, we propose a hippocampal-EC neuronal network model to explore the mechanism of epileptic generation. We demonstrate that enhanced excitability of pyramidal neurons in cornu ammonis 3 (CA3) can drive hippocampal-EC to produce a transition from background to seizure state and cause exaggerated phase-amplitude coupling (PAC) phenomenon of theta modulated high-frequency oscillations (HFO) in CA3, cornu ammonis 1 (CA1), dentate gyrus, and EC. Interestingly, PAC strength indirectly responds to the degree of CA3 pyramidal (PY) neuron hyperexcitability, suggesting that PAC can be used as a potential marker of seizures. Furthermore, we find that enhanced synaptic connectivity of mossy cells to granule cells and CA3 PY neurons drives the system to produce epileptic discharges. These two channels may play a key role in mossy fiber sprouting. In particular, the PAC phenomenon of delta-modulated HFO and theta-modulated HFO can be generated according to the different degrees of moss fiber sprouting. Finally, the results suggest that hyperexcitability of stellate cells in EC can lead to seizures, which supports the argument that EC can act as an independent source of seizures. Overall, these results highlight the key role of different circuits in seizures, providing a theoretical basis and new insights into the generation and propagation of TLE.