Abstract
The role of GABAergic neurotransmission on epileptogenesis has been the subject of speculation according to different approaches. However, it is a very complex task to specifically consider the action of the GABAa neurotransmitter, which, in its dependence on the intracellular level of Cl−, can change its effect from inhibitory to excitatory. We have developed a computational model that represents the dentate gyrus and is composed of three different populations of neurons (granule cells, interneurons and mossy cells) that are mutually interconnected. The interconnections of the neurons were based on compensation theory with Hebbian and anti-Hebbian rules. The model also incorporates non-synaptic mechanisms to control the ionic homeostasis and was able to reproduce ictal discharges. The goal of the work was to investigate the hypothesis that the observed aberrant sprouting is promoted by GABAa excitatory action. Conjointly with the abnormal sprouting of the mossy fibres, the simulations show a reduction of the mossy cells connections in the network and an increased inhibition of the interneurons as a response of the neuronal network to control the activity. This finding contributes to increasing the changes in the connectivity of the neuronal circuitry and to increasing the epileptiform activity occurrences.
Highlights
Epilepsy is the most common chronic neurological disorder, and it is characterized by hyper-synchronization and hyper-excitability of the neuronal network[1,2]
High [Cl−]i promotes a positive shift in the EGABAa, which exhibits an excitatory effect on the post-synaptic membrane
Decreased expression of K+Cl− cotransporter (KCC) has been shown in granule cells after an epileptogenic injury, which is a condition that has a significant effect in favour of intracellular Cl− accumulation and in the subsequent development of epilepsy[11]
Summary
Epilepsy is the most common chronic neurological disorder, and it is characterized by hyper-synchronization and hyper-excitability of the neuronal network[1,2]. Investigations show that in the course of that latent period, several pathophysiological phenomena that lead to epileptogenesis can occur[8,9], like changing in the expression of cotransporters associated with the inflammatory process, reflecting accumulation of intracellular chloride, and cellular swelling, leading to enhanced non-synaptic interconnections. This pathophysiological scenario is favourable to the excitation/inhibition unbalancing and mutual neuronal coupling
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