Reversing Nerve Cell Pathology by Optimizing Modulatory Action on Target Ion Channels
2011 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 101, no 8, 1871-1879 p.Article in journal (Refereed) Published
In diseases of the brain, the distribution and properties of ion channels display deviations from healthy control subjects. We studied three cases of ion channel alteration related to epileptogenesis. The first case of ion channel alteration represents an enhanced sodium current, the second case addresses the downregulation of the transient potassium current K(A), and the third case relates to kinetic properties of K(A) in a patient with temporal lobe epilepsy. Using computational modeling and optimization, we aimed at reversing the pathological characteristics and restoring normal neural function by altering ion channel properties. We identified two key aspects of neural dysfunction in epileptogenesis: an enhanced response to synaptic input in general and to highly synchronized synaptic input in particular. In previous studies, we showed that the potassium channel K(A) played a major role in neural responses to highly synchronized input. It was therefore selected as the target upon which modulators would act. In biophysical simulations, five experimentally characterized endogenous modulations on the K(A) channel were included. Relative concentrations of these modulators were controlled by a numerical optimizer that compared model output to predefined neural output, which represented a normal physiological response. Several solutions that restored the neuron function were found. In particular, distinct subtype compositions of the auxiliary proteins Kv channel-interacting proteins 1 and dipeptidyl aminopeptidase-like protein 6 were able to restore changes imposed by the enhanced sodium conductance or suppressed K(A) conductance. Moreover, particular combinations of protein kinese C, calmodulin-dependent protein kinase II, and arachidonic acid were also able to restore these changes as well as the channel pathology found in a patient with temporal lobe epilepsy. The solutions were further analyzed for sensitivity and robustness. We suggest that the optimization procedure can be used not only for neurons, but also for other organs with excitable cells, such as the heart and pancreas where channelopathies are found.
Place, publisher, year, edition, pages
2011. Vol. 101, no 8, 1871-1879 p.
CA1 PYRAMIDAL NEURONS, TEMPORAL-LOBE EPILEPSY, POTASSIUM CURRENTS, KETOGENIC DIET, K+ CHANNELS, IN-VIVO, RAT, KV4.2, EXCITABILITY, EXPRESSION
Biophysics Neurosciences Bioinformatics (Computational Biology)
IdentifiersURN: urn:nbn:se:kth:diva-47975DOI: 10.1016/j.bpj.2011.08.055ISI: 000296075800010ScopusID: 2-s2.0-80054702134OAI: oai:DiVA.org:kth-47975DiVA: diva2:457182
QC 201111172011-11-172011-11-152012-04-23Bibliographically approved