Computer Simulations Support a Morphological Contribution to BDNF Enhancement of Action Potential Generation.
Brain-derived neurotrophic factor (BDNF) regulates both action potential (AP) generation and neuron morphology. However, whether BDNF-induced changes in neuron morphology directly impact AP generation is unclear. We quantified BDNF's effect on cultured cortical neuron morphological parameters and found that BDNF stimulates dendrite growth and addition of dendrites while increasing both excitatory and inhibitory presynaptic inputs in a spatially restricted manner. To gain insight into how these combined changes in neuron structure and synaptic input impact AP generation, we used the morphological parameters we gathered to generate computational models. Simulations suggest that BDNF-induced neuron morphologies generate more APs under a wide variety of conditions. Synapse and dendrite addition have the greatest impact on AP generation. However, subtle alterations in excitatory/inhibitory synapse ratio and strength have a significant impact on AP generation when synaptic activity is low. Consistent with these simulations, BDNF rapidly enhances spontaneous activity in cortical cultures. We propose that BDNF promotes neuron morphologies that are intrinsically more efficient at translating barrages of synaptic activity into APs, which is a previously unexplored aspect of BDNF's function.
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder Boulder, CO, USA.
Domenico F
DF
Galati
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder Boulder, CO, USA.
Brian G
BG
Hiester
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder Boulder, CO, USA.
Kevin R
KR
Jones
BDNF; computational model; excitatory; inhibitory; plasticity
J Neurosci. 2000 May 1;20(9):3221-32
10777787
J Neurosci. 1998 Sep 15;18(18):7256-71
9736647
Science. 1995 Mar 17;267(5204):1658-62
7886457
Science. 2002 Mar 8;295(5561):1907-10
11884759
Annu Rev Neurosci. 2007;30:425-50
17417940
PLoS Biol. 2008 Jan;6(1):e16
18232737
Neuron. 2013 Mar 20;77(6):1017-38
23522039
Proc Natl Acad Sci U S A. 1990 Oct;87(20):8145-9
2236028
Nat Med. 2012 Mar 18;18(4):564-71
22426422
PLoS One. 2014 Dec 22;9(12):e115298
25531531
J Physiol. 1997 Jan 1;498 ( Pt 1):153-64
9023775
Nature. 1993 May 27;363(6427):350-3
8497318
Cell. 2013 Dec 19;155(7):1596-609
24360280
Science. 2008 Mar 21;319(5870):1683-7
18309046
J Neurosci. 2014 Mar 5;34(10):3475-92
24599449
Neuron. 1996 Apr;16(4):815-23
8607999
Nat Neurosci. 2012 Jan 15;15(3):423-30, S1-3
22246433
Nat Med. 2009 Mar;15(3):331-7
19198615
Mol Cell Neurosci. 2013 Sep;56:115-27
23639831
Cereb Cortex. 2014 Aug;24(8):2178-88
23529006
J Neurosci. 2013 Jul 10;33(28):11618-32
23843530
Neuron. 1995 Oct;15(4):791-803
7576629
Nature. 1996 Jul 25;382(6589):363-6
8684467
BMC Neurosci. 2006 Feb 07;7:11
16464257
Nat Neurosci. 2002 Nov;5(11):1177-84
12368805
Nat Neurosci. 2004 Apr;7(4):373-9
15004561
Nat Rev Neurosci. 2013 Jan;14(1):7-23
23254191
J Neurosci. 2001 Jun 15;21(12):4249-58
11404410
Nat Neurosci. 2002 Apr;5(4):332-40
11896396
Neuron. 2010 Sep 23;67(6):1048-61
20869600
J Neurosci. 2013 Jan 30;33(5):2156-65
23365251
Neuron. 2008 Nov 26;60(4):610-24
19038219
Science. 1995 Apr 14;268(5208):301-4
7716525
Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8856-60
7568031
Nat Rev Neurosci. 2008 Mar;9(3):206-21
18270515
J Neurosci. 2003 Jul 30;23(17):6856-65
12890780
Neuropharmacology. 2014 Jan;76 Pt C:628-38
23752094
Science. 2013 May 10;340(6133):759-62
23661763
J Neurosci Methods. 2011 Feb 15;195(2):185-93
21167201
Curr Opin Neurobiol. 2014 Jun;26:27-33
24650501
J Neurosci. 2011 Nov 9;31(45):16217-26
22072673
Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12547-52
8901619
PLoS Comput Biol. 2012;8(7):e1002599
22829759
Neuron. 1999 Jun;23(2):353-64
10399940
J Physiol. 2008 Apr 1;586(7):1885-901
18238806
Development. 2006 Jul;133(13):2477-86
16728478
Cell. 1999 Sep 17;98(6):739-55
10499792
Annu Rev Neurosci. 2005;28:503-32
16033324
J Neurosci. 2004 Mar 10;24(10):2380-93
15014113
Nat Rev Neurosci. 2000 Dec;1(3):181-90
11257906
Dev Neurobiol. 2010 Apr;70(5):271-88
20186709
Nat Methods. 2012 Jun 28;9(7):676-82
22743772
Nat Neurosci. 2001 Nov;4(11):1093-101
11593233
J Neurosci. 2012 Oct 3;32(40):13644-60
23035077
J Neurosci. 1986 Oct;6(10):3044-60
3760948
Exp Brain Res. 2009 Dec;199(3-4):203-34
19777221
Methods Enzymol. 2012;504:183-200
22264535
Nat Neurosci. 2010 Aug;13(8):967-72
20639875
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8074-7
7644540
Nat Neurosci. 2012 Mar 25;15(5):769-75
22446878
PLoS Comput Biol. 2012;8(6):e1002550
22719240
Proc Natl Acad Sci U S A. 1983 May;80(9):2799-802
6573680
J Neurobiol. 2005 Feb 5;62(2):278-88
15514998
J Neurosci. 2000 Nov 1;20(21):8087-95
11050130
Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19456-61
23129644
Neuron. 2015 May 20;86(4):1041-54
25959732
Nature. 2002 Jul 11;418(6894):177-81
12110889
Front Neuroinform. 2013 Feb 14;7:2
23420185
Neuron. 2009 Jul 30;63(2):171-7
19640476
Neural Dev. 2011 Aug 24;6:31
21864334
J Neurophysiol. 2010 Aug;104(2):1052-60
20554850
Br J Pharmacol. 2008 Mar;153 Suppl 1:S310-24
18059328
Learn Mem. 1999 May-Jun;6(3):284-91
10492010
Neural Comput. 1997 Aug 15;9(6):1179-209
9248061
J Neurophysiol. 1994 Jun;71(6):2183-93
7523612
Nature. 2013 Nov 7;503(7474):121-5
24201284
Neuroreport. 1994 Dec 30;6(1):21-5
7703418
PLoS One. 2012;7(7):e40726
22811762
J Neurosci. 2014 Apr 9;34(15):5370-84
24719114
J Neurophysiol. 2016 Aug 1;116(2):466-71
27146982
J Neurosci. 1998 Dec 1;18(23):9733-50
9822734
J Neurosci. 2005 Jun 29;25(26):6221-34
15987952
J Neurophysiol. 2009 Apr;101(4):1847-66
19176614
Neuropharmacology. 2014 Jan;76 Pt C:610-27
23791959
Nat Rev Drug Discov. 2011 Mar;10(3):209-19
21358740
J Neurosci. 2007 Jul 4;27(27):7234-44
17611276
Science. 2007 Oct 5;318(5847):71-6
17823315
J Neurosci. 2006 Jul 5;26(27):7189-200
16822976
Neuron. 1996 Jun;16(6):1137-45
8663990
J Cell Biol. 2012 Apr 16;197(2):327-37
22492722
Bioinformatics. 2013 Jul 15;29(14):1840-1
23681123