Neuronal basis of brain hypersynchronization in absence seizures: a computational study

Abstract

Absence seizures are generalized epileptic seizures mainly diagnosed and prevalent in children and are caused by abnormal electrical brain activity. These seizures initiate in layer 5/6 of the primary somatosensory cortex and are associated with genetic-based channelopathies. More than thirty mutations in genes encoding T-type calcium channels, with a gain-of-function profile, have been linked to absence epilepsy. These channels are the actual front-line treatment target and have been identified in the axon initial segment (AIS) of the above-mentioned primary somatosensory layer 5 pyramidal cells, a domain that plays a major role in neuronal excitability. AIS T-type calcium channels are crucial for bursting, so that any perturbation could potentially lead to epileptogenesis through increased synchronicity. This thesis aims to understand how T-type calcium channels located in the AIS of neurons lead to bursting and how such bursting affects brain oscillations and their synchronization in the somatosensory cortex network. We have designed and implemented a computational model that will enable us to understand the basic neural mechanisms underlying hypersynchronization states in the initiation foci of absence epileptic seizures. To do that, we describe mathematically somatosensory pyramidal neurons with a compartmentalized integrate-and-fire model, extended to include AIS T-type calcium channels. We also connect these neurons to the two main cortical interneuron populations via conductance-based synapses. Our results show that an upregulation of the T-type calcium channel leads to an increase in synchronized activity in local cortical networks in different oscillatory regimes, explaining how these channels could be responsible for hypersynchrony and seizure initiation.