title: Disruption of basal lamina components in neuromotor synapses of children with spastic quadriplegic cerebral palsy.
abstract: Cerebral palsy (CP) is a static encephalopathy occurring when a lesion to the developing brain results in disordered movement and posture. Patients present with sometimes overlapping spastic, athetoid/dyskinetic, and ataxic symptoms. Spastic CP, which is characterized by stiff muscles, weakness, and poor motor control, accounts for ∼80% of cases. The detailed mechanisms leading to disordered movement in spastic CP are not completely understood, but clinical experience and recent studies suggest involvement of peripheral motor synapses. For example, it is recognized that CP patients have altered sensitivities to drugs that target neuromuscular junctions (NMJs), and protein localization studies suggest that NMJ microanatomy is disrupted in CP. Since CP originates during maturation, we hypothesized that NMJ disruption in spastic CP is associated with retention of an immature neuromotor phenotype later in life. Scoliosis patients with spastic CP or idiopathic disease were enrolled in a prospective, partially-blinded study to evaluate NMJ organization and neuromotor maturation. The localization of synaptic acetylcholine esterase (AChE) relative to postsynaptic acetylcholine receptor (AChR), synaptic laminin β2, and presynaptic vesicle protein 2 (SV2) appeared mismatched in the CP samples; whereas, no significant disruption was found between AChR and SV2. These data suggest that pre- and postsynaptic NMJ components in CP children were appropriately distributed even though AChE and laminin β2 within the synaptic basal lamina appeared disrupted. Follow up electron microscopy indicated that NMJs from CP patients appeared generally mature and similar to controls with some differences present, including deeper postsynaptic folds and reduced presynaptic mitochondria. Analysis of maturational markers, including myosin, syntrophin, myogenin, and AChR subunit expression, and telomere lengths, all indicated similar levels of motor maturation in the two groups. Thus, NMJ disruption in CP was found to principally involve components of the synaptic basal lamina and subtle ultra-structural modifications but appeared unrelated to neuromotor maturational status.
authors: Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America.
authors: Karyn G
authors: KG
authors: Robinson
authors: Janet L
authors: JL
authors: Mendonca
authors: Jaimee L
authors: JL
authors: Militar
authors: Mary C
authors: MC
authors: Theroux
authors: Kirk W
authors: KW
authors: Dabney
authors: Suken A
authors: SA
authors: Shah
authors: Freeman
authors: F
authors: Miller
authors: Robert E
authors: RE
authors: Akins
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D001485:Basement Membrane / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure*; D016022:Case-Control Studies; D002547:Cerebral Palsy / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002648:Child; D005260:Female; D015870:Gene Expression; D006801:Humans; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure*; D011446:Prospective Studies; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure*
chemical_list: D007797:Laminin; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011950:Receptors, Cholinergic; C489616:SV2B protein, human; C058783:laminin beta2; C076414:SV2A protein, human; D000110:Acetylcholinesterase
references: J Cell Biol. 1998 Dec 14;143(6):1713-23
references: 9852162
references: Nature. 2004 Dec 2;432(7017):580-7
references: 15577901
references: Clin Obstet Gynecol. 2008 Dec;51(4):816-28
references: 18981805
references: J Cell Biol. 1997 Feb 24;136(4):883-94
references: 9049253
references: J Histochem Cytochem. 1970 Sep;18(9):670-2
references: 4249441
references: Nucleic Acids Res. 2001 May 1;29(9):e45
references: 11328886
references: J Cell Biol. 2008 Sep 22;182(6):1201-15
references: 18794334
references: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9654-9
references: 9689136
references: J Neurosci. 1986 Jun;6(6):1606-12
references: 3711998
references: J Cell Biol. 1997 Dec 15;139(6):1507-21
references: 9396756
references: J Orthop Res. 1994 Nov;12(6):758-68
references: 7983551
references: Neuromuscul Disord. 1999 Oct;9(6-7):423-33
references: 10545049
references: Pflugers Arch. 2006 Aug;452(5):608-14
references: 16604367
references: Neuroreport. 1992 Oct;3(10):857-60
references: 1421088
references: Biochem J. 2003 Jun 1;372(Pt 2):543-54
references: 12614199
references: Brain. 2006 Aug;129(Pt 8):2061-76
references: 16870884
references: J Neurocytol. 2003 Jun-Sep;32(5-8):743-66
references: 15034265
references: Nat Rev Neurosci. 2001 Nov;2(11):791-805
references: 11715056
references: J Neurol Sci. 1985 Sep;70(2):139-49
references: 4056819
references: J Neurosci Methods. 2010 Aug 30;191(2):158-65
references: 20600319
references: Disabil Rehabil. 2006 Feb 28;28(4):183-91
references: 16467053
references: Muscle Nerve. 2005 May;31(5):594-601
references: 15779003
references: J Physiol. 2003 Feb 15;547(Pt 1):169-79
references: 12562921
references: J Neurobiol. 1993 Nov;24(11):1517-30
references: 8283186
references: Brain. 1992 Apr;115 ( Pt 2):451-78
references: 1351415
references: Nat Neurosci. 2001 Jun;4(6):597-604
references: 11369940
references: Neuromuscul Disord. 2000 Feb;10(2):113-20
references: 10714586
references: Nucleic Acids Res. 2002 May 15;30(10):e47
references: 12000852
references: Anesthesiology. 2002 Feb;96(2):330-5
references: 11818764
references: Lancet. 2004 May 15;363(9421):1619-31
references: 15145637
references: J Neurobiol. 1998 Nov 15;37(3):339-58
references: 9828041
references: Dev Med Child Neurol. 1998 Aug;40(8):520-7
references: 9746004
references: Hum Gene Ther. 1997 Aug 10;8(12):1429-38
references: 9287143
references: Annu Rev Neurosci. 1999;22:389-442
references: 10202544
references: Dev Biol. 1996 Oct 10;179(1):223-38
references: 8873766
references: Cell. 1989 Feb 24;56(4):607-17
references: 2537150
references: Microsc Res Tech. 2000 Nov 1;51(3):247-61
references: 11054875
references: Brain Dev. 2002 Mar;24(2):63-6
references: 11891093
references: J Neurocytol. 2003 Jun-Sep;32(5-8):883-903
references: 15034274
references: BMC Med Genomics. 2009 Jul 14;2:44
references: 19602279
references: Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18189-94
references: 15604144
references: Biochem J. 1988 Feb 15;250(1):307-8
references: 3355518
references: Anesth Analg. 1994 Oct;79(4):761-5
references: 7943788
references: Arch Neurol. 1977 Jul;34(7):396-402
references: 880064
references: J Pediatr. 2009 May;154(5):715-20
references: 19111321
references: Dev Med Child Neurol. 2005 Oct;47(10):713-7
references: 16174321
references: Am J Pathol. 1997 Aug;151(2):621-31
references: 9273822
references: Nature. 1986 May 22-28;321(6068):406-11
references: 2423878
references: Neuron. 1988 Apr;1(2):117-25
references: 3272161
references: J Physiol. 2011 May 15;589(Pt 10):2625-39
references: 21486759
references: J Cell Biol. 1997 Feb 24;136(4):871-82
references: 9049252
references: Muscle Nerve. 2005 Nov;32(5):626-32
references: 16025530
references: J Cell Biol. 1998 Sep 7;142(5):1269-78
references: 9732287
references: Am J Physiol Cell Physiol. 2007 Feb;292(2):C641-57
references: 17092996
references: Nucleic Acids Res. 1989 Aug 11;17(15):6167-79
references: 2771643
references: Nature. 1995 Mar 16;374(6519):258-62
references: 7885444
references: J Muscle Res Cell Motil. 2003;24(8):527-37
references: 14870968
references: Proc Natl Acad Sci U S A. 1983 Jun;80(12):3716-20
references: 6304733
references: Hum Mol Genet. 2006 Apr 15;15(8):1279-89
references: 16531417
references: J Neuropathol Exp Neurol. 2005 Apr;64(4):350-61
references: 15835271
references: Biomed Environ Sci. 2003 Sep;16(3):256-66
references: 14631831
references: J Neurobiol. 2006 May;66(6):522-36
references: 16555236
references: Anaesthesia. 1999 Jun;54(6):593-6
references: 10403876
references: Mol Biol Cell. 2008 Jan;19(1):150-8
references: 17942598
references: Acta Physiol Scand. 2005 May;184(1):3-15
references: 15847639
references: Brain Dev. 1996 Jul-Aug;18(4):299-303
references: 8879649
references: J Med Genet. 2009 Mar;46(3):203-8
references: 19251977
references: Mol Cell Neurosci. 2009 Apr;40(4):433-41
references: 19171194
references: J Physiol. 2003 Feb 1;546(Pt 3):789-800
references: 12563004
references: Am J Anat. 1968 Jan;122(1):145-55
references: 4231725
references: Chem Biol Interact. 2005 Dec 15;157-158:15-21
references: 16289417
references: Neurorehabil Neural Repair. 2007 Nov-Dec;21(6):475-85
references: 17369515
references: Mol Cell Neurosci. 2000 Mar;15(3):262-74
references: 10736203
references: Drug News Perspect. 2007 Sep;20(7):421-9
references: 17992264
references: J Neurosci. 2011 Jan 12;31(2):512-25
references: 21228161
references: Nature. 1998 Jun 18;393(6686):698-701
references: 9641682
references: J Neurosci. 1989 Apr;9(4):1294-302
references: 2539442
references: Eur J Neurosci. 1999 Aug;11(8):2856-64
references: 10457182
references: J Biol Chem. 2010 May 21;285(21):16369-77
references: 20348106