Rho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity.
The Rho GTPase proteins Rac1, RhoA and Cdc42 have a central role in regulating the actin cytoskeleton in dendritic spines, thereby exerting control over the structural and functional plasticity of spines and, ultimately, learning and memory. Although previous work has shown that precise spatiotemporal coordination of these GTPases is crucial for some forms of cell morphogenesis, the nature of such coordination during structural spine plasticity is unclear. Here we describe a three-molecule model of structural long-term potentiation (sLTP) of murine dendritic spines, implicating the localized, coincident activation of Rac1, RhoA and Cdc42 as a causal signal of sLTP. This model posits that complete tripartite signal overlap in spines confers sLTP, but that partial overlap primes spines for structural plasticity. By monitoring the spatiotemporal activation patterns of these GTPases during sLTP, we find that such spatiotemporal signal complementation simultaneously explains three integral features of plasticity: the facilitation of plasticity by brain-derived neurotrophic factor (BDNF), the postsynaptic source of which activates Cdc42 and Rac1, but not RhoA; heterosynaptic facilitation of sLTP, which is conveyed by diffusive Rac1 and RhoA activity; and input specificity, which is afforded by spine-restricted Cdc42 activity. Thus, we present a form of biochemical computation in dendrites involving the controlled complementation of three molecules that simultaneously ensures signal specificity and primes the system for plasticity.
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.
Nathan G
NG
Hedrick
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.
Stephen C
SC
Harward
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.
Charles E
CE
Hall
National Institute for Physiological Science, Myodaiji, Okazaki, Aichi, 444-8585, Japan.
Hideji
H
Murakoshi
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.
James O
JO
McNamara
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.|Max Planck Florida Institute for Neuroscience, 1 Max Planck Way, Jupiter, Florida 33458, USA.
Ryohei
R
Yasuda
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D009433:Neural Inhibition; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057907:Post-Synaptic Density / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D062211:Spatio-Temporal Analysis; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
D019208:Brain-Derived Neurotrophic Factor; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C526380:RhoA protein, mouse; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
Neuron. 2014 Apr 16;82(2):444-59
24742465
J Neurosci. 2005 Apr 13;25(15):3774-86
15829629
Science. 2008 Mar 21;319(5870):1683-7
18309046
Neuropharmacology. 1998 Apr-May;37(4-5):571-9
9704998
Biomed Eng Online. 2003 May 17;2:13
12801419
FEBS Lett. 2003 Mar 27;539(1-3):131-7
12650940
J Biol Chem. 2001 Dec 14;276(50):47530-41
11595749
Neuron. 2009 May 14;62(3):363-74
19447092
Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8856-60
7568031
Sci STKE. 2000 Sep 26;2000(51):pl1
11752611
Nature. 2011 Apr 7;472(7341):100-4
21423166
Neuron. 2009 Apr 30;62(2):254-68
19409270
Nat Neurosci. 2006 Feb;9(2):283-91
16429133
Nature. 2004 Jun 17;429(6993):761-6
15190253
Nat Biotechnol. 2004 Dec;22(12):1567-72
15558047
Nat Neurosci. 2012 Jun;15(6):891-6
22522400
Nat Neurosci. 2004 Oct;7(10):1104-12
15361876
Nature. 2016 Oct 6;538(7623):99-103
27680698
Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10444-9
16801538
Neuron. 2005 Apr 7;46(1):13-21
15820690
Science. 2008 Jul 4;321(5885):136-40
18556515
Nature. 2009 Sep 3;461(7260):99-103
19693013
Mol Cell Neurosci. 2009 Aug;41(4):409-19
19394428
Nat Biotechnol. 2006 Jan;24(1):79-88
16369541
Curr Opin Neurobiol. 2006 Oct;16(5):551-61
16971112
Elife. 2014 Jul 08;3:null
25006034
J Neurosci Methods. 1991 Apr;37(2):173-82
1715499
J Neurosci. 2000 Jul 15;20(14):5329-38
10884317
Neuron. 2004 Jul 8;43(1):31-42
15233915
Brain Cell Biol. 2008 Aug;36(1-4):31-42
18512154
Neuron. 2008 Mar 13;57(5):719-29
18341992
Nature. 2007 Dec 20;450(7173):1195-200
18097401
Nat Neurosci. 2012 Nov;15(11):1506-15
23064382
Mol Cell Biol. 2006 Sep;26(18):6957-70
16943436
Mol Biol Cell. 2010 Jan 1;21(1):165-76
19889835
Cereb Cortex. 2000 Oct;10(10):927-38
11007543