Restoring ion channel pathology by parameter optimization
© Tigerholm and Fransén; licensee BioMed Central Ltd. 2011
Published: 18 July 2011
In diseases of the brain, the distribution and properties of ion channels display deviations from healthy control subjects. We studied two cases of ion channel alterations related to epileptogenesis. The first case of ion channel alteration represents an enhanced sodium current, the second case addresses the run down of conductance of the transient potassium current, KA. In previous studies we have shown that KA reduce highly synchronized synaptic input while minimally affect semi-synchronized input (1). The KA channel may therefore function as a protective mechanism against synchronous input involved in seizures. In this study we investigate if modulatory substances which targets the KA can functionally corrected the two pathological models.
We used a detailed compartmental model of a CA1 pyramidal cell based on a model published by Poolos et al 2002 (2). The model includes sodium, delayed rectifier potassium, A-type potassium and h channel models. On three medial distal dendrites 20 excitatory synaptic inputs were placed. The 20 synaptic inputs had a temporal distribution with different standard deviation corresponding to different levels of synchronicity. The modulation of KA by two substances, KChIP1 and DPP6, was implemented in the model from experimental data. These substances produce shifts of activation, inactivation and time constant curves. Relative concentrations of these modulators were controlled by a numerical optimizer which compared model output to predefined neural output which represented a normal physiological response.
Our simulations show that an increase of KChIP1 or of DPP6 can functionally correct both pathological models’ response to different levels of synchronized input. These modulatory substances could be beneficial in reducing epileptic activity and could be candidates for drug development.
- Fransén E, Tigerholm J: Role of a-type potassium currents in excitability, network synchronicity, and epilepsy. Hippocampus. 2010, 20: 877-887.PubMed CentralPubMedGoogle Scholar
- Poolos NP, Migliore M, Johnston D: Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nature neuroscience. 2002, 5: 767-774.PubMedGoogle Scholar
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