Ion channels and diseases

The consequences of epilepsy causing ion channel mutations in the dentate gyrus

Evan Alexander Thomas, Chris Alan Reid, Steven Petrou

Howard Florey Institute, Parkville, 3010

In recent years hundreds of epilepsy mutations in voltage gated ion channel diseases have been identified. In these cases we know exactly what the cause of the disease so this gives an unprecedented opportunity to understand how brains become epileptic. Part of this process will involve computer modelling of seizure prone networks. An important class of ion channels are the voltage gated sodium channels that are responsible for action potential initiation and propagation. Mutations in these channels affect how they responds to voltage, for examples shifting steady voltage dependence of activation or inactivation or alter gating rates. Some changes are predicted to increase neural excitability while will decrease excitability. Usually several such changes occur simultaneously. In a previous study (Thomas et al, Neuroscience 2007 147:1034-46), we found that shifts in the voltage dependence of activation had the most profound influence on excitability. Left shifts, which increase open probability, dramatically increased firing rate and lowered firing threshold. The simple neuron models were less sensitive to shifts in the voltage dependence of inactivation, and less sensitive again to changes in gating rates. We wished to extend our previous study in two ways. Firstly, we wanted to test in more realistic single neuron models. The simple neuron models that we used previously did not have realistic morphology and had only the minimum number of conductances required to generate action potentials. Secondly, although seizure susceptibility must start with a cellular phenotype, seizures are manifestly a network phenomena. We therefore performed a sensitivity analysis in the dentate gyrus. This structure has been implicated in temporal lobe epilepsy. In order to assess a neuron’s input/output behaviour we stimulated neurons with current injections and measured the resulting firing frequency. In some cases, this produced counterintuitive results. For example, left shifting the steady state voltage dependence of activation might be predicted to increase sodium channel availability and hence increase excitability. However, in response to long current injections the firing rate of neurons with the mutant channels was lower than wild type neurons. This is because increasing sodium channel availability increased action potential amplitude, which in turn, increased the action potential duty cycle increasing the firing frequency. In order to assess network function we stimulated with a constant frequency, random input from the perforant path and measured firing rate averaged across the network. In the control case the network showed moderate accommodation in response to long duration inputs. Left shifting the voltage dependence of activation reduced the accommodation and a right shift increased accommodation. By contrast, altering activation rates and inactivation had little effect. In all cases the network returned to rest on cessation of input and no other stables states were found. In conclusion, the dentate gyrus is unlikely to be the focus of seizures caused by ion channel mutations without additional structural changes. However, mutations will effect how much activity flows into deeper hippocampal structures and this together with changes in these structures may explain hippocampal based seizures.

 Evan Neuroeng 2008 poster (5.64 MB)