Modeling pathogenesis and treatment response in childhood absence epilepsy

Abstract

SummaryObjective: Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for c-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE. Methods: The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABA A , and GABA B synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABA A conductance. Results: Decreasing cortical GABA A conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type. Significance: These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE. K E Y W O R D Scomputer model of epilepsy, multiscale thalamocortical model, polygenic epilepsy

The absence of NIPA2 enhances neural excitability through BK (big potassium) channels

“…Childhood absence epilepsy (CAE) is a common type of genetic generalized epilepsies . Typical clinical manifestations include gazing, transient loss of consciousness, and sudden stop of motion, and they are resolved generally within 30 seconds .…”

NetPyNE, a tool for data-driven multiscale modeling of brain circuits

“…A related concept is that of parameter exploration. Once a model is tuned to reproduce biological features, it is common to explore individual parameters to understand their relation to particular model features, for example how synaptic weights affect network oscillations (Neymotin et al, 2011), or the effect of different pharmacological treatments on pathological symptoms (Neymotin et al, 2016b; Knox et al, 2018).…”

“…Several models published in other languages have been converted to NetPyNE to increase their usability and flexibility. These include models of cortical circuits exploring EEG/MEG signals (https://hnn.brown.edu/) (Jones et al, 2009; Neymotin et al, 2018), interlaminar flow of activity (Potjans and Diesmann, 2014; Romaro et al, 2018) (Figure 9A) and epileptic activity (Knox et al, 2018) (Figure 9B); a dentate gyrus network (Tejada et al, 2014; Rodriguez, 2018) (Figure 9C); and CA1 microcircuits (Cutsuridis et al, 2010; Tepper et al, 2018) (Figure 9D). As a measure of how compact the NetPyNE model definition is, we compared the number of source code lines (excluding comments, blank lines, cell template files and mod files) of the original and NetPyNE implementations (see Table 1).…”

“…( A ) Spike raster plot and boxplot statistics of the Potjans and Diesmann thalamocortical network originally implemented in NEST (Potjans and Diesmann, 2014; Romaro et al, 2018). ( B ) Spike raster plot and voltage traces of a thalamocortical network exhibiting epileptic activity originally implemented in NEURON/hoc (Knox et al, 2018). ( C ) 3D representation of the cell types and network topology, and spike raster plots of a dentate gyrus model originally implemented in NEURON/hoc (Rodriguez, 2018; Tejada et al, 2014).…”

Estimating neuronal conductance model parameters using dynamic action potential clamp

“…For example, the classical Hodgkin Huxley (HH) equations ( 6) are widely used for developing biophysically realistic ion channel conductances that underlie firing in neuronal models (2,7,8). Specifically, HH equations were developed to describe the membrane conductance of the squid giant axon and they have been successfully used to parameterize mammalian neuronal conductances (9)(10)(11)(12)(13) or cells that heterologously express a desired channel type (1,14,15).…”