Light-Induced and Noise-Induced Seizures Reveal the Active Participation of Non-Hippocampal Neuronal Networks in Chronic Temporal Lobe Epilepsy


Student thesis: Doctoral Thesis

View graph of relations

Related Research Unit(s)


Awarding Institution
Award date26 Sep 2022


Epilepsy is a neurological disease that is characterized by recurrent and spontaneous seizures. An imbalance between neuronal excitation and inhibition, which distorts neuronal networks on a structural and functional scale, characterizes the epileptic brain. Hyperexcitability and hypersynchronous firing of a large population of neurons on a micro or macro-circuit scale leads to behavioural deficits that manifest as seizures. On a global scale, approximately 1-2% of the human population suffers from epilepsy, and it affects people of all ages and races, making it the most common and chronic neurological disorder. Temporal lobe epilepsy (TLE) is the most predominant form of acquired epilepsy characterized by hippocampal lesions and is often resistant to drug intervention. Although several studies have attributed epileptic activities in chronic TLE to the hippocampus, the participation of non-hippocampal neuronal networks in disease progression is often neglected. Unravelling the participation of non-hippocampal mechanisms involved in TLE could facilitate the development of novel antiepileptic drugs.

In this dissertation, the kainic acid (KA) mouse model of chronic TLE was adopted in studying non-hippocampal network activities in chronic TLE. To begin with, we injected KA into the dorsal hippocampus to generate chronic TLE mice. Immunohistochemical staining of Fos-positive neurons after a spontaneous seizure in the chronic stage of TLE revealed an intense expression of c-Fos in the hippocampus and non-hippocampal cells. Non-hippocampal cells showing prominent c-Fos expression include cortical areas such as the motor cortex (MCx), visual cortex (VCx), and auditory cortex (ACx). This reveals that chronic TLE's seizure activity faithfully recruits non-hippocampal brain areas, including the cortex.

Hyperexcitability is a hallmark of epilepsy. The perturbation of such hyperexcitable networks can make them unstable and breakdown into seizures. We exposed TLE mice to light or noise stimulation after an induction period and found that flashlight or noise can trigger seizure onset in chronic TLE mice during and after stimulation. And the frequency of these light-induced or noise-induced seizures depends on the stimulus modality adopted during the induction period. The occurrence of seizures resulting from light or noise stimulation suggests the active participation of cortical networks in the initiation and propagation of such epileptic activities.

Furthermore, we sought to unravel the seizure onset zone (SOZ) of the recorded light-induced and noise-induced seizures. To do this, we adopted a combined behavior and multiple-site electrophysiology by recording local field potentials (LFP) from the MCx, VCx, ACx, and hippocampus simultaneously. Analysis of LFP seizure waves reveals the existence of hippocampal and cortical SOZ. We found that most of the light-induced seizures had their SOZ in the VCx while most of the noise-induced seizures had their SOZ in the ACx. In addition, we discovered that inter-ictal spikes (IIS) were present in the hippocampus and were also seen in the cortical areas. The frequency of these IIS discharge increased in response to light or noise stimulation both in the hippocampus and cortex, revealing that cortical networks are also hyperexcited in chronic TLE. This hyperexcitation can trigger seizure onset with a non-hippocampal seizure focus.

Whether the occurrence of cortical epileptic activities, especially the epileptic spikes (ES), is restricted to the chronic stage of TLE or not was further investigated. We employed multiple-site electrophysiology (recording of LFP in MCx, VCx and hippocampus) and hippocampal KA infusion via cannula to understand the developmental profile of epileptic spikes from baseline physiology to latent stage and chronic stage of TLE. We found that the infusion of KA into the hippocampus causes a dramatic increase in the frequency of ES across days far above baseline values within the hippocampus as well as in the recorded cortical areas (MCx and VCx). Also, the frequency of these ES was sustained into the chronic stage and could not return to baseline physiology. This reveals that the recruitment of non-hippocampal cortical networks in TLE occurs faster than previously thought. This remote hyperexcitable network that develops during the latent stage predisposes the epileptic brain to have a secondary epileptic focus in the chronic stage of the disease independent of the hippocampus.

In order to ascertain whether epileptic seizures can occur independent of the hippocampus in chronic TLE mice, we surgically removed the KA-injected hippocampus and found that mouse showed seizure freedom for some days after which relapse of seizure occurred. There was no significant change in the frequency of seizure recurrence when compared with pre-surgical seizure frequency. In addition, we further demonstrated that chemical removal of bilateral hippocampus in chronic TLE mice also could not permanently halt epileptic seizure initiation in these mice. Meaning that seizures can be initiated in secondary epileptic foci after hippocampi removal which reveals the fundamental role of non-hippocampal networks in generating epileptic activities with or without the hippocampus in the chronic stage of TLE.

Therefore, the study of TLE should not exclude the participation of non-hippocampal networks, particularly cortical networks, in the progression of the disease. Our study provides additional insight into the need for a comprehensive therapeutic approach that includes suppressing epileptic activities in the cortex, not just those targeting the hippocampus alone in treating TLE.

    Research areas

  • Epilepsy, seizure, seizure onset zone, c-Fos, hippocampus, cortex