title: Thyroid hormone-dependent development of early cortical networks: temporal specificity and the contribution of trkB and mTOR pathways.
abstract: Early in neocortical network development, triiodothyronine (T3) promotes GABAergic neurons' population increase, their somatic growth and the formation of GABAergic synapses. In the presence of T3, GABAergic interneurons form longer axons and conspicuous axonal arborizations, with an increased number of putative synaptic boutons. Here we show that the increased GABAergic axonal growth is positively correlated with the proximity to non-GABAergic neurons (non-GABA). A differential innervation emerges from a T3-dependent decrease of axonal length in fields with low density of neuronal cell bodies, combined with an increased bouton formation in fields with high density of neuronal somata. T3 addition to deprived networks after the first 2 weeks of development did not rescue deficits in the GABAergic synaptic bouton distribution, or in the frequency and duration of spontaneous bursts. During the critical 2-week-period, GABAergic signaling is depolarizing as revealed by calcium imaging experiments. Interestingly, T3 enhanced the expression of the potassium-chloride cotransporter 2 (KCC2), and accelerated the developmental shift from depolarizing to hyperpolarizing GABAergic signaling in non-GABA. The T3-related increase of spontaneous network activity was remarkably reduced after blockade of either tropomyosin-receptor kinase B (trkB) or mammalian target of rapamycin (mTOR) pathways. T3-dependent increase in GABAergic neurons' soma size was mediated mainly by mTOR signaling. Conversely, the T3-dependent selective increase of GABAergic boutons near non-GABAergic cell bodies is mediated by trkB signaling only. Both trkB and mTOR signaling mediate T3-dependent reduction of the GABAergic axon extension. The circuitry context is relevant for the interaction between T3 and trkB signaling, but not for the interactions between T3 and mTOR signaling.
authors: Institute of Physiology, Otto-von-Guericke University Magdeburg, Germany.
authors: Sören
authors: S
authors: Westerholz
authors: Ana D
authors: AD
authors: de Lima
authors: Thomas
authors: T
authors: Voigt
keywords: BDNF; GABA; KCC2; NKCC1; interneurons; mTOR; neocortex; triiodothyronine
references: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3985-9
references: 11891331
references: Neuropharmacology. 2010 Jun;58(7):1130-9
references: 20153760
references: Nature. 2002 Oct 17;419(6908):687-93
references: 12384689
references: J Neurophysiol. 2006 Mar;95(3):2007-12
references: 16306179
references: Development. 2003 Apr;130(7):1267-80
references: 12588844
references: J Neurosci. 2006 Nov 8;26(45):11720-5
references: 17093093
references: Endocrinology. 2007 Jan;148(1):92-102
references: 17008398
references: Neurosci Res. 1993 Feb;16(2):95-103
references: 8387174
references: Nat Neurosci. 2001 Nov;4 Suppl:1207-14
references: 11687831
references: Cell. 2001 May 18;105(4):521-32
references: 11371348
references: J Neurosci. 2003 Sep 24;23(25):8722-32
references: 14507972
references: Childs Nerv Syst. 2010 Nov;26(11):1495-504
references: 20358377
references: Prog Neurobiol. 2003 Apr;69(5):341-74
references: 12787574
references: Neuron. 2009 Mar 26;61(6):820-38
references: 19323993
references: Thyroid. 2003 Nov;13(11):1005-12
references: 14651784
references: Nature. 1999 Oct 28;401(6756):918-21
references: 10553907
references: J Neurobiol. 1999 Jun 15;39(4):558-68
references: 10380077
references: Mol Endocrinol. 2009 Sep;23(9):1494-504
references: 19460859
references: J Neurosci. 2009 Sep 2;29(35):10890-9
references: 19726647
references: Physiol Rev. 2007 Oct;87(4):1215-84
references: 17928584
references: Endocrinology. 2012 Mar;153(3):1311-6
references: 22253429
references: Cereb Cortex. 1997 Jun;7(4):303-16
references: 9177762
references: J Physiol. 2009 May 1;587(Pt 9):1873-9
references: 19153158
references: J Endocrinol. 2011 Jun;209(3):261-72
references: 21292729
references: Trends Mol Med. 2011 Dec;17(12):734-42
references: 21890410
references: J Neurosci. 2001 Nov 15;21(22):8895-905
references: 11698601
references: J Neurosci. 2009 Mar 18;29(11):3419-30
references: 19295148
references: J Neurosci. 2009 May 27;29(21):6964-72
references: 19474323
references: Neurobiol Dis. 2010 Oct;40(1):193-9
references: 20566381
references: Nat Rev Neurosci. 2010 Jan;11(1):18-29
references: 19953103
references: Neuroscience. 2013 Jun 3;239:253-70
references: 23201250
references: Endocr Rev. 1997 Aug;18(4):462-75
references: 9267760
references: Biochim Biophys Acta. 2010 Mar;1804(3):433-9
references: 20005306
references: Eur J Neurosci. 2008 May;27(9):2402-12
references: 18430034
references: Nat Neurosci. 2000 Apr;3(4):366-71
references: 10725926
references: Front Neural Circuits. 2009 Oct 20;3:15
references: 19876404
references: J Neurochem. 2005 Dec;95(5):1438-45
references: 16171514
references: Neurosci Lett. 2008 Aug 15;441(1):50-5
references: 18586400
references: Epilepsia. 2007 Apr;48(4):834-6
references: 17284292
references: Biochim Biophys Acta. 2008 Jan;1784(1):116-32
references: 17913600
references: Nat Med. 2005 Nov;11(11):1205-13
references: 16227993
references: Endocr Rev. 2008 Dec;29(7):898-938
references: 18815314
references: Rev Neurosci. 1996 Apr-Jun;7(2):85-101
references: 8819204
references: J Clin Invest. 2011 Apr;121(4):1596-607
references: 21403402
references: Nat Rev Neurosci. 2002 Sep;3(9):715-27
references: 12209120
references: Genes Dev. 2005 Sep 15;19(18):2152-63
references: 16131613
references: J Neurocytol. 1983 Aug;12(4):697-712
references: 6619907
references: Front Cell Neurosci. 2010 Jun 21;4:15
references: 20617185
references: J Neurosci Res. 2010 May 15;88(7):1420-32
references: 20029971
references: J Neurosci. 2005 Jan 12;25(2):331-42
references: 15647476
references: Exp Brain Res. 1998 Mar;119(1):1-8
references: 9521530
references: J Neurosci. 2004 Aug 18;24(33):7366-77
references: 15317862
references: Neuroscientist. 2006 Feb;12(1):43-56
references: 16394192
references: Nat Neurosci. 2000 May;3(5):452-9
references: 10769384
references: J Neurosci. 2003 Jul 2;23(13):5662-73
references: 12843269
references: Science. 1980 Oct 10;210(4466):153-7
references: 7414326
references: Mol Psychiatry. 2003 Jan;8(1):30-8
references: 12556906
references: Endocrinology. 2010 Feb;151(2):810-20
references: 20056827
references: Nat Clin Pract Endocrinol Metab. 2007 Mar;3(3):249-59
references: 17315033
references: Eur J Neurosci. 2004 Jun;19(11):2931-43
references: 15182300
references: Neurosci Lett. 2011 May 20;495(3):201-4
references: 21458538
references: J Comp Neurol. 2006 Nov 1;499(1):132-43
references: 16958091
references: Eur J Neurosci. 2008 Dec;28(12):2371-80
references: 19087168
references: Curr Opin Neurobiol. 2009 Apr;19(2):231-4
references: 19545994
references: Trends Endocrinol Metab. 2000 May-Jun;11(4):123-8
references: 10754532
references: J Neuroendocrinol. 2008 Dec;20(12):1319-38
references: 19094080
references: Curr Opin Neurobiol. 1999 Feb;9(1):94-104
references: 10072366
references: J Neuroendocrinol. 2008 Jun;20(6):784-94
references: 18601701
references: J Neurosci. 2008 Nov 26;28(48):12851-63
references: 19036979
references: J Neurophysiol. 2002 Nov;88(5):2196-206
references: 12424261
references: J Neurosci. 2011 Feb 9;31(6):2337-47
references: 21307269
references: Nat Neurosci. 2004 Nov;7(11):1184-6
references: 15475951
references: Eur J Neurosci. 2007 Jan;25(1):1-16
references: 17241262
references: Neurosci Res. 1994 Jul;20(1):85-94
references: 7984343
references: J Physiol. 2005 Jan 1;562(Pt 1):27-36
references: 15528236
references: Nat Rev Neurosci. 2005 Dec;6(12):955-65
references: 16288299
references: Eur J Neurosci. 2005 May;21(9):2593-9
references: 15932617
references: Nucl Recept Signal. 2006;4:e020
references: 16862226
references: Neuroscience. 1992;47(2):409-20
references: 1641131
references: J Proteome Res. 2007 Mar;6(3):1059-71
references: 17330943
references: Neuron. 1991 Mar;6(3):333-44
references: 1672071
references: Neuroscience. 2010 Jun 30;168(2):573-89
references: 20338226
references: Steroids. 2010 Dec;75(12):988-97
references: 20600205
references: J Neurosci. 2005 May 4;25(18):4605-15
references: 15872108
references: Science. 2010 Aug 20;329(5994):959-64
references: 20724638
references: J Neurosci. 2007 Oct 17;27(42):11334-42
references: 17942728
references: Neurochem Res. 2008 Jun;33(6):1065-76
references: 18097751
references: J Comp Neurol. 1997 Dec 1;388(4):526-40
references: 9388013
references: Brain Res. 2010 Feb 8;1313:9-24
references: 20018181
references: Neurotoxicology. 2012 Aug;33(4):842-52
references: 22138353
references: J Neurophysiol. 2005 Mar;93(3):1557-68
references: 15469961
references: EMBO J. 1990 Nov;9(11):3545-50
references: 2170117
references: J Neurosci. 2004 Mar 24;24(12):2853-65
references: 15044524
references: Am J Physiol. 1995 Dec;269(6 Pt 1):C1496-505
references: 8572179
references: Mol Neurobiol. 2011 Apr;43(2):97-106
references: 21042953
references: J Neurosci. 2008 Feb 20;28(8):1904-15
references: 18287507
references: Science. 1996 Nov 15;274(5290):1133-8
references: 8895456
references: J Physiol. 2009 May 1;587(Pt 9):1881-8
references: 19188247
references: J Neurosci. 2004 Oct 27;24(43):9598-611
references: 15509747
references: Cell Signal. 2008 Apr;20(4):659-65
references: 18207367
references: Nat Rev Neurosci. 2007 Sep;8(9):673-86
references: 17704810
references: J Neurosci. 2004 Jan 14;24(2):522-30
references: 14724252
references: J Endocrinol. 2011 Apr;209(1):1-8
references: 21212091
references: Oncogene. 1992 Feb;7(2):371-81
references: 1312698
references: Trends Neurosci. 2010 Feb;33(2):67-75
references: 19963289
references: Proc Biol Sci. 1997 Mar 22;264(1380):367-73
references: 9107052
references: Eur J Neurosci. 1999 Nov;11(11):3845-56
references: 10583473
references: Neuroscience. 2004;126(4):955-66
references: 15207329
references: Cereb Cortex. 2004 Mar;14(3):342-51
references: 14754872
references: Nature. 1999 Jan 21;397(6716):251-5
references: 9930699
references: J Neurosci. 1996 Oct 15;16(20):6414-23
references: 8815920
references: Epilepsia. 2011 Nov;52(11):2057-64
references: 21883182
references: Neuroscience. 2004;125(2):369-79
references: 15062980
references: J Neurosci. 2010 Dec 1;30(48):16220-31
references: 21123568
references: Ann Neurol. 2007 Feb;61(2):139-52
references: 17279540
references: Mol Cell Endocrinol. 2008 Jun 11;287(1-2):1-12
references: 18448240
references: J Neurosci. 2009 May 27;29(21):6982-8
references: 19474325
references: J Cell Biol. 1996 May;133(3):631-46
references: 8636237
references: Cell Calcium. 2005 May;37(5):451-7
references: 15820393
references: J Neurophysiol. 2011 Sep;106(3):1500-14
references: 21697440
references: Cereb Cortex. 2012 Sep;22(9):2111-9
references: 22021912
references: Front Neurosci. 2010 Dec 08;4:201
references: 21151823
references: Neurosci Lett. 2003 Oct 30;350(3):141-4
references: 14550914
references: J Neurosci. 2009 Jun 24;29(25):8259-69
references: 19553465
references: J Neurosci. 1997 Jun 15;17(12):4527-35
references: 9169513
references: J Neurosci. 2007 May 9;27(19):5224-35
references: 17494709
references: Endocrinology. 1999 Sep;140(9):3955-61
references: 10465264
references: Thyroid. 2001 Mar;11(3):205-10
references: 11327610
references: Invest Ophthalmol Vis Sci. 2006 Feb;47(2):673-82
references: 16431967
references: Synapse. 2007 Mar;61(3):138-49
references: 17146765
references: Neuron. 1995 Dec;15(6):1287-98
references: 8845153