The modeling of drug-induced changes in ion channel kinetics and firing properties in fast-spiking interneurons: a computational study

Abstract: Interneurons have been found to be important for normal cognitive function. Impairments to their growth or signaling have been indicated to be involved in the development of schizophrenia, autism and epilepsy. Defective functioning in GABA:ergic interneurons has been linked to undesired desynchronous firing in neural signals as a consequence of these interneurons firing too infrequently or not at all. A sodium current activator (AA43279) targeted towards the sodium ion channel Nav1.1 in the neuronal membrane has been suggested as a tool compound to study sodium channels. In this project, Hodgkin-Huxley models have been produced to model the Nav1.1 ion channels in a drugged condition (30 uM) and a control condition (no drug) to evaluate its effect on Nav1.1 channel kinetics. The models can accurately reproduce the sodium currents in a specific voltage clamp protocol for step potentials between -20 mV and 40 mV. The neuron models produce the qualitative appearance expected when modeling changes in membrane potential in response to current injection. The drug's mode of action was hypothesized to be caused by it increasing sodium current for all membrane potentials, shortening the duration for recovery from action potentials as well as increasing the duration over which the sodium influx into neurons decays. More measurements are needed to make the models valid for membrane potentials below -20 mV and accurate for potentials above 40 mV. Future work may involve expanding the model to a multi-compartment model.