Weston, Mikail Jehan; (2024) Chemogenetic dissection of the mechanisms of secondary epileptogenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Epilepsy is defined as a disease of the brain characterized by a predisposition to generate epileptic seizures: the transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. It is the commonest serious neurological condition affecting people of any age with over 70 million worldwide. Most of the disease burden of falls on the 20-30% with drug resistant epilepsy (DRE). The commonest DRE is mesial temporal lobe epilepsy (MTLE), where seizures start in the temporal lobe and can be treated with surgical resection but may fail due to secondary seizure generating areas. Epileptogenesis is the process whereby a brain insult instigates spontaneous recurrent seizures (SRSs) (i.e. epilepsy). Secondary epileptogenesis or progressive worsening of epilepsy, is significant for therapies and induces drugs or surgery to fail. It is unknown if secondary epileptogenesis depends on ongoing SRSs akin to kindling, or if it can evolve independently following an initial intense seizure. The chemogenetic DREADD (Designer Receptor Exclusively Activated by a Designer Drug), hM4D(Gi), induces on-demand neuronal inhibition via metabolically inert clozapine-N-oxide (CNO) and other drugs and is a promising novel therapy for DRE. This project utilised DREADDs to assess the aetiology of secondary epileptogenesis. The in vivo efficacy of the clinically approved drug olanzapine on hM4D(Gi) was validated with a mouse motor task. Models of rodent MTLE, induced by intracerebral kainic acid were replicated and characterised. Using Neuropixels high density silicon probes, seizure onset site was assessed in a mouse model of MTLE and hM4D(Gi), efficacy at acute seizure suppression induced by olanzapine was proven. This technology shows great promise as a clinical treatment in focal epilepsy due to its reduced invasiveness. This is important for potential treatment in humans, as the procedures are less invasive than resective surgery.

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