title: Glutamatergic axon-derived BDNF controls GABAergic synaptic differentiation in the cerebellum.
abstract: To study mechanisms that regulate the construction of inhibitory circuits, we examined the role of brain-derived neurotrophic factor (BDNF) in the assembly of GABAergic inhibitory synapses in the mouse cerebellar cortex. We show that within the cerebellum, BDNF-expressing cells are restricted to the internal granular layer (IGL), but that the BDNF protein is present within mossy fibers which originate from cells located outside of the cerebellum. In contrast to deletion of TrkB, the cognate receptor for BDNF, deletion of Bdnf from cerebellar cell bodies alone did not perturb the localization of pre- or postsynaptic constituents at the GABAergic synapses formed by Golgi cell axons on granule cell dendrites within the IGL. Instead, we found that BDNF derived from excitatory mossy fiber endings controls their differentiation. Our findings thus indicate that cerebellar BDNF is derived primarily from excitatory neurons--precerebellar nuclei/spinal cord neurons that give rise to mossy fibers--and promotes GABAergic synapse formation as a result of release from axons. Thus, within the cerebellum the preferential localization of BDNF to axons enhances the specificity through which BDNF promotes GABAergic synaptic differentiation.
authors.affiliation: University of California, San Francisco, Department of Physiology and Neuroscience Program, San Francisco, CA 94158, USA.|Nanyang Technological University, School of Biological Sciences and Warwick-NTU Neuroscience Programme, Singapore 138673.|University of Warwick, School of Life Sciences, Coventry CV4 7AL, UK.|Institute of Molecular and Cell Biology, Singapore 138673.
authors.forename: Albert I
authors.initials: AI
authors.lastname: Chen
authors.affiliation: University of California, San Francisco, Department of Physiology and Neuroscience Program, San Francisco, CA 94158, USA.
authors.forename: Keling
authors.initials: K
authors.lastname: Zang
authors.affiliation: University of California, San Diego, Department of Neurosciences, San Diego, CA 92093, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: University of California, San Francisco, Department of Physiology and Neuroscience Program, San Francisco, CA 94158, USA.
authors.forename: Louis F
authors.initials: LF
authors.lastname: Reichardt
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002531:Cerebellum / Q000502:physiology*; D058967:Contactin 1 / Q000235:genetics / Q000378:metabolism; D059330:GABAergic Neurons / Q000502:physiology*; D015870:Gene Expression; D018698:Glutamic Acid / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009411:Nerve Endings / Q000378:metabolism; D009412:Nerve Fibers / Q000378:metabolism; D021381:Protein Transport; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D058967:Contactin 1; D011963:Receptors, GABA-A; D018698:Glutamic Acid
references.citation: Nat Genet. 1999 Jan;21(1):70-1
references.pmid: 9916792
references.citation: Clin Sci (Lond). 2006 Feb;110(2):167-73
references.pmid: 16411893
references.citation: Science. 2008 Mar 21;319(5870):1683-7
references.pmid: 18309046
references.citation: Neuron. 2011 May 12;70(3):385-409
references.pmid: 21555068
references.citation: J Neurosci. 2013 Jun 12;33(24):9957-62
references.pmid: 23761891
references.citation: Neuron. 2014 Dec 3;84(5):1009-22
references.pmid: 25467984
references.citation: Cell. 2003 Jan 24;112(2):257-69
references.pmid: 12553913
references.citation: Cell. 2004 Aug 20;118(4):517-28
references.pmid: 15315763
references.citation: Mol Cell Neurosci. 2013 Sep;56:115-27
references.pmid: 23639831
references.citation: Nat Rev Neurosci. 2014 Mar;15(3):141-56
references.pmid: 24552784
references.citation: J Neurosci. 2001 Aug 15;21(16):6170-80
references.pmid: 11487640
references.citation: Curr Biol. 1998 Dec 3;8(24):1323-6
references.pmid: 9843687
references.citation: Nature. 1994 Mar 10;368(6467):147-50
references.pmid: 8139657
references.citation: Mol Endocrinol. 2001 Oct;15(10):1748-57
references.pmid: 11579207
references.citation: J Neurosci. 2002 Feb 15;22(4):1316-27
references.pmid: 11850459
references.citation: Nat Neurosci. 2005 Aug;8(8):1069-77
references.pmid: 16025106
references.citation: J Neurosci. 2010 Feb 3;30(5):1739-49
references.pmid: 20130183
references.citation: Nat Neurosci. 2009 Jun;12(6):767-76
references.pmid: 19448629
references.citation: J Neurosci. 2005 Oct 12;25(41):9535-43
references.pmid: 16221864
references.citation: Genes Dev. 1996 Nov 15;10(22):2849-58
references.pmid: 8918886
references.citation: J Neurosci. 2011 Jul 20;31(29):10602-14
references.pmid: 21775604
references.citation: Philos Trans R Soc Lond B Biol Sci. 2006 Sep 29;361(1473):1545-64
references.pmid: 16939974
references.citation: Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):E65-72
references.pmid: 25535349
references.citation: Neuron. 2013 Oct 2;80(1):97-112
references.pmid: 24035762
references.citation: Neuron. 2008 Nov 26;60(4):610-24
references.pmid: 19038219
references.citation: Neurochem Int. 2014 Jun;72:14-21
references.pmid: 24747341
references.citation: Mol Cell Biol. 2011 Aug;31(16):3326-38
references.pmid: 21690300
references.citation: J Neurosci. 2011 Aug 17;31(33):11894-904
references.pmid: 21849550
references.citation: Nat Neurosci. 2002 Mar;5(3):225-33
references.pmid: 11836532
references.citation: BMC Dev Biol. 2001;1:4
references.pmid: 11299042
references.citation: J Neurosci. 2011 Feb 23;31(8):2769-80
references.pmid: 21414899
references.citation: J Neurosci. 2012 Jan 4;32(1):99-110
references.pmid: 22219273
references.citation: Cerebellum. 2013 Jun;12(3):328-30
references.pmid: 23341142
references.citation: J Neurosci. 2012 Apr 4;32(14):4790-802
references.pmid: 22492034
references.citation: Cell. 1993 Oct 8;75(1):113-22
references.pmid: 8402890
references.citation: Learn Mem. 1999 May-Jun;6(3):276-83
references.pmid: 10492009
references.citation: Perspect Dev Neurobiol. 1997;5(1):83-94
references.pmid: 9509520
references.citation: J Comp Neurol. 1997 Feb 3;378(1):135-57
references.pmid: 9120052
references.citation: Int J Biochem Cell Biol. 2007;39(10):1930-42
references.pmid: 17618159
references.citation: J Neurosci. 1997 Apr 1;17(7):2295-313
references.pmid: 9065491
references.citation: Neuron. 2000 Oct;28(1):41-51
references.pmid: 11086982
references.citation: J Neurosci. 2007 Mar 7;27(10):2472-82
references.pmid: 17344385
references.citation: Nat Neurosci. 2008 Jun;11(6):649-58
references.pmid: 18382462
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1267-72
references.pmid: 19147841
references.citation: J Neurosci Methods. 1991 Apr;37(2):173-82
references.pmid: 1715499
references.citation: Anat Embryol (Berl). 1988;179(1):81-8
references.pmid: 3213958
references.citation: Cell. 2009 Oct 2;139(1):161-74
references.pmid: 19804761
references.citation: Nat Cell Biol. 2003 Jan;5(1):38-45
references.pmid: 12510192
references.citation: Cell. 2008 Jul 11;134(1):175-87
references.pmid: 18614020
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5942-7
references.pmid: 19293383
references.citation: Nature. 2013 Nov 7;503(7474):121-5
references.pmid: 24201284
references.citation: Front Synaptic Neurosci. 2014 Mar 31;6:6
references.pmid: 24744726
references.citation: J Clin Invest. 2007 Apr;117(4):931-43
references.pmid: 17380209
references.citation: Neuron. 2007 Jul 5;55(1):53-68
references.pmid: 17610817
references.citation: J Neurosci Res. 2005 Mar 1;79(5):616-27
references.pmid: 15672445
references.citation: Front Cell Neurosci. 2014 Apr 11;8:107
references.pmid: 24782711
references.citation: Curr Opin Neurobiol. 2011 Apr;21(2):306-12
references.pmid: 21450454
references.citation: Neuroscience. 2012 Jun 14;212:1-18
references.pmid: 22542678
references.citation: J Cell Biol. 2012 Mar 19;196(6):775-88
references.pmid: 22412021