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

Cahlin, Alexander LU (2018) BMEM01 20181
Department of Biomedical Engineering
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... (More)
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. (Less)
Popular Abstract
Models reveal how a drug can "boost" our brain cells
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This project's models showed that a "booster-drug" increased neurons' firing rate and sensitivity to stimulation, by affecting a specific ion channel in the cell membrane.
Please use this url to cite or link to this publication:
author
Cahlin, Alexander LU
supervisor
organization
course
BMEM01 20181
year
type
H2 - Master's Degree (Two Years)
subject
keywords
Modeling, Hodgkin-Huxley, Nav1.1, VGSC, SCN1A, interneurons, AA43279, 3-amino-5-(4-methoxyphenyl)thiophene-2-carboxamide, electrophysiology.
language
English
id
8951740
date added to LUP
2018-06-21 12:54:39
date last changed
2018-06-21 12:54:39
@misc{8951740,
  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.}},
  author       = {{Cahlin, Alexander}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{The modeling of drug-induced changes in ion channel kinetics and firing properties in fast-spiking interneurons: a computational study}},
  year         = {{2018}},
}