title: Mossy fiber sprouting interacts with sodium channel mutations to increase dentate gyrus excitability.
abstract: OBJECTIVE
  Idiopathic epilepsy is caused by the complex interaction of genetic and environmental factors. The purpose of this study was to use computational approaches to explore the interaction between changes in sodium channel availability caused by mutations and mossy fiber sprouting.
  
  
  METHODS
  We used a previously published biophysically realistic computer model of dentate gyrus neurons and networks. A sensitivity analysis probed the effects of typical mutation-like changes in either single- or multiple-gating parameters. Isolated neuron models were stimulated with current injections, and networks were stimulated with perforant path synaptic input. The gene-environment interaction was studied by including mossy fiber sprouting into these networks.
  
  
  RESULTS
  Single neuron responses to current injections were complex, with increased sodium channel availability paradoxically reducing firing rates. In the absence of mossy fiber sprouting, control networks showed strong accommodation supporting the role of the dentate gyrus as a gate. Availability changes alone were not able to drive the networks into ictal states, even though they reduced the effectiveness of the dentate gyrus gate. Interestingly, the presence of electrophysiologic changes substantially increased the ability of mossy fiber sprouting to induce ictal activity.
  
  
  CONCLUSIONS
  (1) Increased sodium channel availability does not necessarily lead to increased firing rates, (2) network excitability is most sensitive to changes in steady state activation of sodium channels, (3) mutation-induced changes in availability reduce the effectiveness of the dentate gyrus gate, and (4) mutations interact strongly with structural network changes to allow ictal-like activity in the dentate gyrus.
authors.affiliation: Howard Florey Institute, Parkville, Victoria, Australia. evan@evan-thomas.net
authors.forename: Evan A
authors.initials: EA
authors.lastname: Thomas
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reid
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D020864:Calcium Channels, N-Type / Q000502:physiology; D003198:Computer Simulation; D018891:Dentate Gyrus / Q000166:cytology / Q000502:physiology* / Q000503:physiopathology; D004558:Electric Stimulation; D004833:Epilepsy, Temporal Lobe / Q000209:etiology / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D019599:Mossy Fibers, Hippocampal / Q000502:physiology*; D009154:Mutation / Q000235:genetics* / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology; D016571:Neural Networks, Computer; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D019580:Perforant Pathway / Q000502:physiology; D051381:Rats; D012640:Seizures / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
chemical_list: D020864:Calcium Channels, N-Type; C470379:SCN1B protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit