The use of automated parameter searches to improve ion channel kinetics for neural modeling.
The voltage and time dependence of ion channels can be regulated, notably by phosphorylation, interaction with phospholipids, and binding to auxiliary subunits. Many parameter variation studies have set conductance densities free while leaving kinetic channel properties fixed as the experimental constraints on the latter are usually better than on the former. Because individual cells can tightly regulate their ion channel properties, we suggest that kinetic parameters may be profitably set free during model optimization in order to both improve matches to data and refine kinetic parameters. To this end, we analyzed the parameter optimization of reduced models of three electrophysiologically characterized and morphologically reconstructed globus pallidus neurons. We performed two automated searches with different types of free parameters. First, conductance density parameters were set free. Even the best resulting models exhibited unavoidable problems which were due to limitations in our channel kinetics. We next set channel kinetics free for the optimized density matches and obtained significantly improved model performance. Some kinetic parameters consistently shifted to similar new values in multiple runs across three models, suggesting the possibility for tailored improvements to channel models. These results suggest that optimized channel kinetics can improve model matches to experimental voltage traces, particularly for channels characterized under different experimental conditions than recorded data to be matched by a model. The resulting shifts in channel kinetics from the original template provide valuable guidance for future experimental efforts to determine the detailed kinetics of channel isoforms and possible modulated states in particular types of neurons.
Biomedical Engineering Department, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Eric B
EB
Hendrickson
Jeremy R
JR
Edgerton
Dieter
D
Jaeger
D000200:Action Potentials / Q000502:physiology; D000465:Algorithms; D000818:Animals; D002462:Cell Membrane / Q000502:physiology*; D005917:Globus Pallidus / Q000166:cytology / Q000502:physiology*; D019044:Image Cytometry / Q000379:methods; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000493:pharmacokinetics / Q000502:physiology*; D007700:Kinetics; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques / Q000379:methods; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D012984:Software; D055366:Synaptic Potentials / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
D007473:Ion Channels
Physiology (Bethesda). 2008 Feb;23:49-57
18268365
Nat Neurosci. 2006 Mar;9(3):356-62
16444270
Neural Netw. 2005 Jun-Jul;18(5-6):488-96
16095875
Biol Cybern. 2008 Nov;99(4-5):371-9
19011925
J Neurosci. 1998 May 15;18(10):3521-8
9570783
J Neurosci. 2000 Jan 15;20(2):579-88
10632587
J Physiol. 2009 Feb 15;587(Pt 4):829-49
19124538
J Neurosci. 2007 Dec 5;27(49):13552-66
18057213
J Neurosci. 1996 Nov 1;16(21):6676-86
8824308
Biol Cybern. 2008 Nov;99(4-5):241-51
19011918
J Neurosci. 2004 Jan 14;24(2):329-40
14724231
J Neurophysiol. 2009 Oct;102(4):2288-302
19675296
J Neurosci. 2008 Jul 23;28(30):7476-91
18650326
Physiol Rev. 2000 Oct;80(4):1483-521
11015619
Nat Genet. 2003 Nov;35(3):258-63
14566338
Eur J Neurosci. 2006 May;23(10):2551-62
16817858
J Neurosci. 1998 May 15;18(10):3501-10
9570781
J Neurosci. 2002 Apr 15;22(8):3100-7
11943813
Nature. 2007 Jan 4;445(7123):E1-2; discussion E2-3
17203021
J Physiol. 2001 Sep 1;535(Pt 2):445-72
11533136
J Biol Chem. 1995 Dec 1;270(48):28495-8
7499357
J Comput Neurosci. 2011 Apr;30(2):301-21
20623167
J Neurophysiol. 2008 Mar;99(3):1127-36
18184885
J Neurophysiol. 2005 Dec;94(6):3730-42
16093338
J Comput Neurosci. 1999 Sep-Oct;7(2):149-71
10515252
Science. 2006 Aug 18;313(5789):976-9
16917065
Nat Neurosci. 2008 Feb;11(2):178-86
18204443
J Comput Neurosci. 2008 Jun;24(3):358-73
17999167
Adv Second Messenger Phosphoprotein Res. 1999;33:23-48
10218113
PLoS Comput Biol. 2006 Jul 21;2(7):e94
16848639
J Neurophysiol. 2003 Dec;90(6):3998-4015
12944532
Biophys J. 2004 Oct;87(4):2380-96
15454437
J Neurosci. 2009 Apr 29;29(17):5573-86
19403824
J Neurosci. 2003 Sep 10;23(23):8261-70
12967988
Biophys J. 2000 Jul;79(1):314-20
10866957
Brain Res Bull. 2000 Mar 15;51(5):393-9
10715559