title: Loss of corticostriatal and thalamostriatal synaptic terminals precedes striatal projection neuron pathology in heterozygous Q140 Huntington's disease mice.
abstract: Motor slowing, forebrain white matter loss, and striatal shrinkage have been reported in premanifest Huntington's disease (HD) prior to overt striatal neuron loss. We carried out detailed LM and EM studies in a genetically precise HD mimic, heterozygous Q140 HD knock-in mice, to examine the possibility that loss of corticostriatal and thalamostriatal terminals prior to striatal neuron loss underlies these premanifest HD abnormalities. In our studies, we used VGLUT1 and VGLUT2 immunolabeling to detect corticostriatal and thalamostriatal (respectively) terminals in dorsolateral (motor) striatum over the first year of life, prior to striatal projection neuron pathology. VGLUT1+ axospinous corticostriatal terminals represented about 55% of all excitatory terminals in striatum, and VGLUT2+ axospinous thalamostriatal terminals represented about 35%, with VGLUT1+ and VGLUT2+ axodendritic terminals accounting for the remainder. In Q140 mice, a significant 40% shortfall in VGLUT2+ axodendritic thalamostriatal terminals and a 20% shortfall in axospinous thalamostriatal terminals were already observed at 1 month of age, but VGLUT1+ terminals were normal in abundance. The 20% deficiency in VGLUT2+ thalamostriatal axospinous terminals persisted at 4 and 12 months in Q140 mice, and an additional 30% loss of VGLUT1+ corticostriatal terminals was observed at 12 months. The early and persistent deficiency in thalamostriatal axospinous terminals in Q140 mice may reflect a development defect, and the impoverishment of this excitatory drive to striatum may help explain early motor defects in Q140 mice and in premanifest HD. The loss of corticostriatal terminals at 1 year in Q140 mice is consistent with prior evidence from other mouse models of corticostriatal disconnection early during progression, and can explain both the measurable bradykinesia and striatal white matter loss in late premanifest HD.
authors: Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors: Y P
authors: YP
authors: Deng
authors: T
authors: T
authors: Wong
authors: C
authors: C
authors: Bricker-Anthony
authors: B
authors: B
authors: Deng
authors: A
authors: A
authors: Reiner
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000648:ultrastructure*; D003342:Corpus Striatum / Q000648:ultrastructure*; D055879:Gene Knock-In Techniques; D006816:Huntington Disease / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000648:ultrastructure*; D013788:Thalamus / Q000648:ultrastructure*; D013997:Time Factors; D050598:Vesicular Glutamate Transport Protein 1 / Q000032:analysis / Q000276:immunology; D050599:Vesicular Glutamate Transport Protein 2 / Q000032:analysis / Q000276:immunology
chemical_list: D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2
keywords: Corticostriatal; Huntington's disease; Pathology; Premanifest; Thalamostriatal
references: J Neural Transm (Vienna). 2007 Mar;114(3):367-72
references: 17024326
references: Eur J Neurosci. 2002 Jun;15(12):1918-28
references: 12099898
references: Trends Neurosci. 1989 Oct;12(10):366-75
references: 2479133
references: Acta Neuropathol. 1996;91(2):161-8
references: 8787149
references: Exp Neurol. 2002 Jul;176(1):55-65
references: 12093082
references: J Chem Neuroanat. 2004 Jun;27(3):143-64
references: 15183201
references: Cereb Cortex. 1998 Oct-Nov;8(7):602-13
references: 9823481
references: Lancet Neurol. 2011 Jan;10(1):31-42
references: 21130037
references: Acta Neuropathol. 2008 Jan;115(1):55-69
references: 17978822
references: J Neurol. 2009 Feb;256(2):203-12
references: 19266143
references: Arch Neurol. 1996 Jun;53(6):487-92
references: 8660148
references: Neurology. 1973 Jun;23(6):561-9
references: 4267989
references: J Comp Neurol. 2006 May 10;496(2):202-13
references: 16538675
references: Neurosci Lett. 2007 Oct 2;425(3):195-9
references: 17868995
references: Neurobiol Dis. 2010 Dec;40(3):544-54
references: 20688164
references: Proc Natl Acad Sci U S A. 1988 Aug;85(15):5733-7
references: 2456581
references: Eur J Neurosci. 2001 Nov;14(9):1492-504
references: 11722611
references: Mov Disord. 2000 May;15(3):552-60
references: 10830423
references: Neurobiol Dis. 2011 Jun;42(3):475-81
references: 21382492
references: Brain. 2008 Jan;131(Pt 1):196-204
references: 18056161
references: Brain Res Mol Brain Res. 1998 Jun 15;57(2):257-65
references: 9675424
references: Eur J Neurosci. 2004 Dec;20(12):3322-30
references: 15610164
references: J Neurophysiol. 2001 Dec;86(6):2667-77
references: 11731527
references: Biol Psychiatry. 2006 Jan 1;59(1):57-63
references: 16112655
references: Mov Disord. 2007 Sep 15;22(12):1783-9
references: 17579363
references: Front Syst Neurosci. 2011 Jun 16;5:46
references: 21720523
references: AJNR Am J Neuroradiol. 2004 Nov-Dec;25(10):1715-21
references: 15569736
references: Hum Mol Genet. 2011 Oct 15;20(20):3899-909
references: 21775500
references: Brain. 2007 Nov;130(Pt 11):2858-67
references: 17893097
references: Brain Res Bull. 2012 Apr 10;87(6):571-8
references: 22326483
references: Mov Disord. 2009 Sep 15;24(12):1763-72
references: 19562761
references: J Chem Neuroanat. 2007 Jul;33(4):167-92
references: 17446041
references: J Neurol Neurosurg Psychiatry. 2010 Jul;81(7):756-63
references: 19955112
references: AJNR Am J Neuroradiol. 2010 Nov;31(10):1807-12
references: 20813872
references: Arch Neurol. 2000 Jul;57(7):1040-4
references: 10891987
references: Neuroscience. 2000;97(3):505-19
references: 10828533
references: Neurosci Lett. 1991 Dec 9;133(2):257-61
references: 1840078
references: Arch Neurol. 1996 Dec;53(12):1293-6
references: 8970459
references: Neurology. 1991 Jul;41(7):1117-23
references: 1829794
references: J Neurosci. 2011 Jan 26;31(4):1170-82
references: 21273402
references: J Comp Neurol. 1987 May 1;259(1):65-91
references: 3294930
references: Brain Res Bull. 2004 Mar 1;63(1):45-55
references: 15121238
references: J Comp Neurol. 1987 Sep 22;263(4):567-80
references: 2822779
references: Acta Neuropathol. 1993;85(5):553-9
references: 8493863
references: Neuroimage. 2006 Oct 1;32(4):1562-75
references: 16875847
references: J Neurosci. 2009 Feb 25;29(8):2414-27
references: 19244517
references: Arch Neurol. 1992 Nov;49(11):1161-7
references: 1444883
references: Nat Neurosci. 2011 Dec 18;15(2):215-23
references: 22179111
references: Annu Rev Neurosci. 1992;15:285-320
references: 1575444
references: J Neurol Neurosurg Psychiatry. 2011 Apr;82(4):405-10
references: 20884680
references: Brain Res. 2012 Sep 14;1473:161-72
references: 22820300
references: Neuroscience. 2001;103(1):87-96
references: 11311789
references: J Neurosci. 2001 Nov 15;21(22):RC181
references: 11698619
references: CNS Neurosci Ther. 2009 Winter;15(1):1-11
references: 19228174
references: AJNR Am J Neuroradiol. 2010 Jun;31(6):1036-41
references: 20150305
references: Brain. 2011 Jan;134(Pt 1):137-42
references: 20923788
references: Arch Neurol. 1997 Nov;54(11):1353-7
references: 9362982
references: Neurology. 2005 Sep 13;65(5):745-7
references: 16157910
references: Trends Neurosci. 2004 Sep;27(9):520-7
references: 15331233
references: Hum Brain Mapp. 2012 Sep;33(9):2161-73
references: 22887827
references: J Neurol Neurosurg Psychiatry. 2004 Feb;75(2):213-20
references: 14742591
references: Mov Disord. 2006 Sep;21(9):1317-25
references: 16755582
references: Ann Neurol. 1997 Aug;42(2):215-21
references: 9266732
references: J Neurol Sci. 2011 Aug 15;307(1-2):60-8
references: 21624624
references: Eur J Neurol. 2008 Nov;15(11):1180-90
references: 18754766
references: J Neurosci. 1983 Feb;3(2):383-8
references: 6822869
references: ASN Neuro. 2010 Jun 18;2(3):e00036
references: 20585470
references: J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):379-84
references: 19726414
references: J Neurosci. 2007 Oct 24;27(43):11758-68
references: 17959817
references: Exp Neurol. 1994 Sep;129(1):37-56
references: 7925841
references: Brain Res Bull. 2009 Feb 16;78(2-3):60-8
references: 18805468
references: Neurobiol Dis. 2012 Jul;47(1):75-91
references: 22472187
references: Neuroscience. 2008 Nov 11;157(1):280-95
references: 18805465
references: J Neurosci. 2009 Feb 18;29(7):2193-204
references: 19228972
references: Front Neuroanat. 2010 Oct 25;4:142
references: 21088706
references: Neuroscience. 1999 Jan;88(1):119-33
references: 10051194
references: Neuroreport. 2004 Feb 9;15(2):363-5
references: 15076769
references: Neurology. 2010 Dec 14;75(24):2150-60
references: 21068430
references: Arch Neurol. 1999 May;56(5):563-8
references: 10328251
references: J Neurosci. 2004 Mar 17;24(11):2633-42
references: 15028755
references: Eur J Neurosci. 2008 Feb;27(3):671-82
references: 18279319
references: J Neurosci. 2011 Nov 23;31(47):17169-79
references: 22114284
references: Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8727-32
references: 10411943
references: Neuroscience. 2007 Jun 29;147(2):354-72
references: 17544587
references: J Comp Neurol. 2006 Jun 1;496(4):544-55
references: 16572432
references: J Neurol. 2008 Nov;255(11):1785-91
references: 19156490
references: J Comp Neurol. 2001 Feb 19;430(4):485-500
references: 11169482
references: J Comp Neurol. 2007 Dec 20;505(6):603-29
references: 17948889
references: Brain Res Brain Res Rev. 1990 Sep-Dec;15(3):251-65
references: 1981156
references: J Nucl Med. 2006 Feb;47(2):215-22
references: 16455626
references: Neurology. 2003 May 27;60(10):1615-20
references: 12771251
references: Mov Disord. 2008 Jun 15;23(8):1100-7
references: 18412252
references: Cereb Cortex. 1996 Nov-Dec;6(6):759-70
references: 8922332
references: Acta Neuropathol. 1999 Jun;97(6):613-22
references: 10378380
references: J Neurosci. 2002 Jan 1;22(1):142-55
references: 11756497
references: J Comp Neurol. 1990 Sep 8;299(2):187-228
references: 2172326
references: Gait Posture. 2011 Jun;34(2):202-7
references: 21616667
references: J Neurosci. 2003 Feb 1;23(3):961-9
references: 12574425
references: Psychiatry Res. 2005 Oct 30;140(1):55-62
references: 16199141
references: J Neuropathol Exp Neurol. 1985 Nov;44(6):559-77
references: 2932539
references: J Comp Neurol. 2004 Jan 6;468(2):190-204
references: 14648679
references: Front Neural Circuits. 2013 Feb 18;7:19
references: 23423362
references: Trends Neurosci. 1994 Feb;17(2):52-7
references: 7512768
references: J Neuropathol Exp Neurol. 1988 Sep;47(5):516-25
references: 2971785
references: J Neuropathol Exp Neurol. 2004 Jan;63(1):20-31
references: 14748558
references: Vision Res. 2004 Oct;44(23):2729-36
references: 15358067
references: J Chem Neuroanat. 2006 Dec;32(2-4):101-16
references: 16914290
references: Neurology. 1976 Jan;26(1):64-8
references: 128708
references: J Neurosci. 1998 Nov 1;18(21):8648-59
references: 9786972
references: Ann Neurol. 1991 Oct;30(4):542-9
references: 1838677
references: J Mot Behav. 2011;43(4):295-302
references: 21774606
references: Hum Brain Mapp. 2012 Jan;33(1):203-12
references: 21264990
references: Neuroscience. 2006;137(1):327-36
references: 16257492
references: Ann Neurol. 1990 Feb;27(2):200-4
references: 2138444
references: J Neuropathol Exp Neurol. 1998 May;57(5):369-84
references: 9596408
references: J Neurosci. 2011 Nov 9;31(45):16102-6
references: 22072662
references: J Comp Neurol. 2013 Apr 15;521(6):1354-77
references: 23047588
references: Exp Brain Res. 1982;45(1-2):157-67
references: 7056322
references: Neurobiol Dis. 2002 Aug;10(3):378-86
references: 12270698
references: Mov Disord. 2011 Apr;26(5):862-9
references: 21394785
references: Exp Neurol. 2008 Sep;213(1):137-44
references: 18588876
references: J Neurol Neurosurg Psychiatry. 2005 May;76(5):650-5
references: 15834021
references: J Comp Neurol. 2003 Oct 6;465(1):11-26
references: 12926013
references: Ann Neurol. 1995 Dec;38(6):852-61
references: 8526457
references: Neuroscience. 2001;103(3):653-61
references: 11274785
references: Hum Mol Genet. 2007 Aug 1;16(15):1845-61
references: 17519223
references: Neuron. 2001 Aug 2;31(2):247-60
references: 11502256
references: Trends Neurosci. 2004 Feb;27(2):98-103
references: 15102489
references: Exp Neurol. 2011 Apr;228(2):173-82
references: 21192926
references: J Neurocytol. 2004 Sep;33(5):517-33
references: 15906159
references: J Neurophysiol. 1994 Jan;71(1):17-32
references: 8158226
references: Mol Chem Neuropathol. 1997 Jun;31(2):97-118
references: 9376025
references: J Comp Neurol. 2005 Nov 28;492(4):495-509
references: 16228991
references: J Neurosci. 2004 Sep 22;24(38):8289-99
references: 15385612
references: Exp Neurol. 2000 Dec;166(2):307-23
references: 11085896
references: Neurology. 1994 May;44(5):823-8
references: 8190282
references: Brain Res. 1996 Feb 19;709(2):311-5
references: 8833768
references: J Comp Neurol. 2003 Mar 17;457(4):420-40
references: 12561080
references: Neuroscience. 1993 Dec;57(3):661-71
references: 8309529