Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in Mecp2-null mice.
Postnatal deficits in brain-derived neurotrophic factor (BDNF) are thought to contribute to pathogenesis of Rett syndrome (RTT), a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2-null mice, a model of RTT, BDNF deficits are most pronounced in structures important for autonomic and respiratory control, functions that are severely affected in RTT patients. However, relatively little is known about how these deficits affect neuronal function or how they may be linked to specific RTT endophenotypes. To approach these issues, we analyzed synaptic function in the brainstem nucleus tractus solitarius (nTS), the principal site for integration of primary visceral afferent inputs to central autonomic pathways and a region in which we found markedly reduced levels of BDNF in Mecp2 mutants. Our results demonstrate that the amplitude of spontaneous miniature and evoked EPSCs in nTS neurons is significantly increased in Mecp2-null mice and, accordingly, that mutant cells are more likely than wild- type cells to fire action potentials in response to primary afferent stimulation. These changes occur without any increase in intrinsic neuronal excitability and are unaffected by blockade of inhibitory GABA currents. However, this synaptopathy is associated with decreased BDNF availability in the primary afferent pathway and can be rescued by application of exogenous BDNF. On the basis of these findings, we hypothesize that altered sensory gating in nTS contributes to cardiorespiratory instability in RTT and that nTS is a site at which restoration of normal BDNF signaling could help reestablish normal homeostatic controls.
Kline
David D
DD
Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211, USA.
Ogier
Michael
M
Kunze
Diana L
DL
Katz
David M
DM
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D005071:Evoked Potentials / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D066298:In Vitro Techniques; D008526:Medulla Oblongata / Q000502:physiology; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D009475:Neurons, Afferent / Q000502:physiology; D015518:Rett Syndrome; D017552:Solitary Nucleus / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D014795:Visual Pathways / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D005680:gamma-Aminobutyric Acid
Hum Mol Genet. 2007 Mar 15;16(6):640-50
17309881
J Neurophysiol. 2002 Nov;88(5):2736-44
12424308
J Neurosci. 2000 Oct 1;20(19):7417-23
11007900
Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):55-63
18534925
J Neurosci. 1997 Apr 1;17(7):2295-313
9065491
Respir Physiol Neurobiol. 2005 Nov 15;149(1-3):99-109
16203214
Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12560-5
16116096
Respir Physiol Neurobiol. 2009 Aug 31;168(1-2):101-8
19394452
J Neurophysiol. 1986 May;55(5):1076-90
3012009
Respir Physiol Neurobiol. 2009 Aug 31;168(1-2):109-18
19524074
Brain Res Mol Brain Res. 1996 May;38(1):63-70
8737668
J Neurosci. 2003 Aug 20;23(20):7685-9
12930808
Nat Genet. 2001 Mar;27(3):327-31
11242118
Annu Rev Physiol. 1994;56:93-116
7912060
J Physiol. 2008 May 1;586(9):2331-43
18339694
J Neurophysiol. 2008 Apr;99(4):1712-22
18272881
J Physiol. 2007 Mar 15;579(Pt 3):863-76
17204503
Pediatr Pulmonol. 2008 Nov;43(11):1045-1060
18831533
Pediatr Res. 2006 Apr;59(4 Pt 1):513-8
16549521
J Neurochem. 1999 May;72(5):1930-8
10217270
J Neurosci. 2000 Mar 1;20(5):1904-11
10684891
Neuron. 2007 Nov 8;56(3):422-37
17988628
J Neurosci. 2006 Oct 18;26(42):10911-5
17050729
Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):105-11
18524694
J Neurosci. 1999 Mar 15;19(6):2131-42
10066266
J Neurosci. 2005 Mar 30;25(13):3389-99
15800194
J Neurophysiol. 2008 Jan;99(1):112-21
18032561
Neuron. 2006 Feb 2;49(3):341-8
16446138
Brain Res. 2007 Apr 13;1141:119-32
17291467
J Physiol. 2005 Jan 15;562(Pt 2):535-51
15539399
Eur J Neurosci. 2007 Dec;26(12):3449-57
18052976
Hippocampus. 2008;18(3):294-309
18058824
Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):72-9
18620081
J Neurosci. 2007 Oct 3;27(40):10912-7
17913925
Neuron. 2007 Oct 4;56(1):58-65
17920015
J Physiol. 2007 Aug 15;583(Pt 1):315-27
17569735
Neurosci Lett. 2008 Dec 5;447(1):82-6
18834926
Brain Res. 1992 May 29;581(2):339-43
1382802
J Neurophysiol. 2001 May;85(5):2213-23
11353036