Modelling the Effect of Allopregnanolone on the Resolution of Spike-Wave Discharges

Abstract

ObjectiveChildhood absence epilepsy (CAE) is a paediatric generalized epilepsy disorder with a confounding feature of resolving in adolescence in a majority of cases. In this study, we modelled how the small-scale (synapse-level) effect of progesterone metabolite allopregnanolone induces a large-scale (network-level) effect on a thalamocortical circuit associated with this disorder. In particular, our goal was to understand the role of sex steroid hormones in the spontaneous remission of CAE. MethodsThe conductance-based computational model consisted of single-compartment cortical pyramidal, cortical interneurons, thalamic reticular and thalamocortical relay neurons, each described by a set of ordinary differential equations. Excitatory and inhibitory synapses were mediated by AMPA, GABAa and GABAb receptors. The model was implemented using the NetPyne modelling tool and the NEURON simulator. ResultsThe action of allopregnanolone on individual GABAa-receptor mediated synapses has an ameliorating effect on spike-wave discharges (SWDs) associated with absence seizures. This effect is region-specific and most significant in the thalamus, particularly the synapses between thalamic reticular neurons. SignificanceThe remedying effect of allopregnanolone on SWDs may possibly be true only for individuals that are predisposed to remission due to intrinsic connectivity differences or differences in tonic inhibition. These results are a useful first-step and prescribe directions for further investigation into the role of ALLO together with these differences to distinguish between models for CAE-remitting and non-remitting individuals.