title: Organelle and cellular abnormalities associated with hippocampal heterotopia in neonatal doublecortin knockout mice.
abstract: Heterotopic or aberrantly positioned cortical neurons are associated with epilepsy and intellectual disability. Various mouse models exist with forms of heterotopia, but the composition and state of cells developing in heterotopic bands has been little studied. Dcx knockout (KO) mice show hippocampal CA3 pyramidal cell lamination abnormalities, appearing from the age of E17.5, and mice suffer from spontaneous epilepsy. The Dcx KO CA3 region is organized in two distinct pyramidal cell layers, resembling a heterotopic situation, and exhibits hyperexcitability. Here, we characterized the abnormally organized cells in postnatal mouse brains. Electron microscopy confirmed that the Dcx KO CA3 layers at postnatal day (P) 0 are distinct and separated by an intermediate layer devoid of neuronal somata. We found that organization and cytoplasm content of pyramidal neurons in each layer were altered compared to wild type (WT) cells. Less regular nuclei and differences in mitochondria and Golgi apparatuses were identified. Each Dcx KO CA3 layer at P0 contained pyramidal neurons but also other closely apposed cells, displaying different morphologies. Quantitative PCR and immunodetections revealed increased numbers of oligodendrocyte precursor cells (OPCs) and interneurons in close proximity to Dcx KO pyramidal cells. Immunohistochemistry experiments also showed that caspase-3 dependent cell death was increased in the CA1 and CA3 regions of Dcx KO hippocampi at P2. Thus, unsuspected ultrastructural abnormalities and cellular heterogeneity may lead to abnormal neuronal function and survival in this model, which together may contribute to the development of hyperexcitability.
authors.affiliation: INSERM UMRS 839, Paris, France ; Université Pierre et Marie Curie, Paris, France ; Institut du Fer à Moulin, Paris, France.
authors.forename: Reham
authors.initials: R
authors.lastname: Khalaf-Nazzal
authors.forename: Elodie
authors.initials: E
authors.lastname: Bruel-Jungerman
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Rio
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Bureau
authors.forename: Theano
authors.initials: T
authors.lastname: Irinopoulou
authors.forename: Iffat
authors.initials: I
authors.lastname: Sumia
authors.forename: Audrey
authors.initials: A
authors.lastname: Roumegous
authors.forename: Elodie
authors.initials: E
authors.lastname: Martin
authors.forename: Robert
authors.initials: R
authors.lastname: Olaso
authors.forename: Carlos
authors.initials: C
authors.lastname: Parras
authors.forename: Carmen
authors.initials: C
authors.lastname: Cifuentes-Diaz
authors.forename: Fiona
authors.initials: F
authors.lastname: Francis
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D053148:Caspase 3 / Q000378:metabolism; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*
chemical_list: C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D053148:Caspase 3
references.citation: J Neurophysiol. 2007 Nov;98(5):2737-46
references.pmid: 17881479
references.citation: Eur J Neurosci. 2010 Jun;31(12):2136-41
references.pmid: 20529125
references.citation: J Comp Neurol. 2005 Mar 14;483(3):329-40
references.pmid: 15682392
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11794-9
references.pmid: 19561297
references.citation: Cell. 1998 Jan 9;92(1):63-72
references.pmid: 9489700
references.citation: J Neurosci. 2006 May 31;26(22):5901-9
references.pmid: 16738232
references.citation: Cell. 1998 Jan 9;92(1):51-61
references.pmid: 9489699
references.citation: Mol Cell. 2004 Jun 18;14(6):833-9
references.pmid: 15200960
references.citation: Brain Res. 1982 Aug;256(4):379-93
references.pmid: 7127145
references.citation: PLoS One. 2008 Jun 25;3(6):e2473
references.pmid: 18575605
references.citation: Nat Genet. 1998 Aug;19(4):333-9
references.pmid: 9697693
references.citation: Clin Chem. 2009 Apr;55(4):611-22
references.pmid: 19246619
references.citation: J Comp Neurol. 1972 Nov;146(3):277-302
references.pmid: 5086674
references.citation: Brain Struct Funct. 2011 Nov;216(4):301-17
references.pmid: 21597968
references.citation: Eur J Neurosci. 2005 Feb;21(3):611-21
references.pmid: 15733080
references.citation: Mol Cell. 2012 Sep 14;47(5):707-21
references.pmid: 22857951
references.citation: J Neurosci. 2000 Apr 1;20(7):2439-50
references.pmid: 10729324
references.citation: J Comp Neurol. 1992 Aug 22;322(4):501-18
references.pmid: 1401246
references.citation: J Neurosci Res. 1990 Nov;27(3):400-7
references.pmid: 2097382
references.citation: BMC Neurosci. 2010 Dec 31;11:158
references.pmid: 21194452
references.citation: Brain Res Brain Res Rev. 2005 Sep;49(2):227-41
references.pmid: 16111552
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14662-7
references.pmid: 18787118
references.citation: Nature. 2007 Jan 11;445(7124):168-76
references.pmid: 17151600
references.citation: Neuron. 2010 Jan 14;65(1):7-19
references.pmid: 20152109
references.citation: Proc Natl Acad Sci U S A. 1990 Jun;87(11):4393-5
references.pmid: 2349244
references.citation: J Comp Neurol. 2007 Jan 10;500(2):239-54
references.pmid: 17111359
references.citation: J Neurosci. 2008 Aug 6;28(32):8138-43
references.pmid: 18685038
references.citation: Cell Mol Life Sci. 1999 Aug 15;55(10):1206-15
references.pmid: 10487203
references.citation: Nature. 1993 Aug 19;364(6439):717-21
references.pmid: 8355785
references.citation: Eur J Neurosci. 2012 Feb;35(3):366-74
references.pmid: 22288477
references.citation: Nat Genet. 2000 Sep;26(1):93-6
references.pmid: 10973257
references.citation: J Neurosci. 2010 Jun 16;30(24):8320-31
references.pmid: 20554883
references.citation: Cell. 2007 May 4;129(3):579-91
references.pmid: 17482550
references.citation: Development. 1994 Dec;120(12):3379-94
references.pmid: 7821210
references.citation: Hippocampus. 2006;16(12):1032-60
references.pmid: 17094147
references.citation: Microsc Res Tech. 2008 Sep;71(9):633-8
references.pmid: 18459132
references.citation: Hum Mol Genet. 2006 May 1;15(9):1387-400
references.pmid: 16571605
references.citation: Hum Mol Genet. 1998 Jul;7(7):1063-70
references.pmid: 9618162
references.citation: Brain. 1999 Feb;122 ( Pt 2):219-38
references.pmid: 10071051
references.citation: Mol Cell Neurosci. 2001 Sep;18(3):307-19
references.pmid: 11591131
references.citation: Neuron. 2006 Jan 5;49(1):41-53
references.pmid: 16387638
references.citation: Exp Brain Res. 2006 Aug;173(2):322-33
references.pmid: 16724181
references.citation: Neuron. 2000 Dec;28(3):727-40
references.pmid: 11163262
references.citation: Ann Neurol. 1994 Oct;36(4):609-17
references.pmid: 7524438
references.citation: Exp Neurol. 1999 Apr;156(2):254-67
references.pmid: 10328934
references.citation: Neuron. 1999 Jun;23(2):247-56
references.pmid: 10399932
references.citation: EMBO J. 2006 Oct 4;25(19):4448-57
references.pmid: 16957770
references.citation: Anat Embryol (Berl). 1980;159(2):199-210
references.pmid: 7447037
references.citation: Eur J Neurosci. 2012 Jan;35(2):244-56
references.pmid: 22250815
references.citation: Cell. 2007 Jan 12;128(1):45-57
references.pmid: 17218254
references.citation: Nat Neurosci. 2011 Apr;14(4):495-504
references.pmid: 21358645
references.citation: J Neuropathol Exp Neurol. 1999 Jan;58(1):92-106
references.pmid: 10068317
references.citation: Nat Rev Genet. 2002 May;3(5):342-55
references.pmid: 11988760
references.citation: J Neurocytol. 1979 Dec;8(6):697-718
references.pmid: 120417
references.citation: Am J Pathol. 2004 Sep;165(3):775-84
references.pmid: 15331402
references.citation: Brain Res. 2008 Dec 3;1243:27-37
references.pmid: 18824157
references.citation: Acta Neuropathol. 1992;83(3):246-59
references.pmid: 1557956
references.citation: J Comp Neurol. 1990 Nov 15;301(3):343-64
references.pmid: 2262595
references.citation: Mol Neurobiol. 2011 Aug;44(1):83-92
references.pmid: 21691713
references.citation: Development. 1997 Dec;124(24):4959-70
references.pmid: 9362459
references.citation: Acta Neuropathol. 2012 Feb;123(2):189-203
references.pmid: 22179580
references.citation: J Comp Neurol. 1979 Jun 1;185(3):423-59
references.pmid: 86549
references.citation: Am J Pathol. 2001 Oct;159(4):1477-94
references.pmid: 11583975
references.citation: J Neurosci. 2002 Sep 1;22(17):7548-57
references.pmid: 12196578
references.citation: J Comp Neurol. 1990 Nov 15;301(3):325-42
references.pmid: 2262594
references.citation: Acta Neuropathol. 2000 Oct;100(4):403-8
references.pmid: 10985699
references.citation: Glia. 2011 Nov;59(11):1588-99
references.pmid: 21766338
references.citation: J Histochem Cytochem. 2008 Feb;56(2):175-82
references.pmid: 17998568
references.citation: Neuron. 2008 Dec 26;60(6):1010-21
references.pmid: 19109908
references.citation: J Neurosci. 2009 Jan 14;29(2):313-27
references.pmid: 19144832
references.citation: J Cell Biol. 2010 Nov 1;191(3):463-70
references.pmid: 20974813
references.citation: Neuron. 2011 Aug 25;71(4):695-709
references.pmid: 21867885
references.citation: Adv Anat Embryol Cell Biol. 1998;150:1-106
references.pmid: 9816727
references.citation: Brain. 2013 Jan;136(Pt 1):223-44
references.pmid: 23365099
references.citation: J Neurosci. 2011 Jul 27;31(30):10948-70
references.pmid: 21795545
references.citation: Neuron. 1999 Jun;23(2):257-71
references.pmid: 10399933