title: Chronic desipramine treatment rescues depression-related, social and cognitive deficits in Engrailed-2 knockout mice.
abstract: Engrailed-2 (En2) is a homeobox transcription factor that regulates neurodevelopmental processes including neuronal connectivity and elaboration of monoaminergic neurons in the ventral hindbrain. We previously reported abnormalities in brain noradrenergic concentrations in En2 null mutant mice that were accompanied by increased immobility in the forced swim test, relevant to depression. An EN2 genetic polymorphism has been associated with autism spectrum disorders, and mice with a deletion in En2 display social abnormalities and cognitive deficits that may be relevant to multiple neuropsychiatric conditions. This study evaluated the ability of chronic treatment with desipramine (DMI), a selective norepinephrine (NE) reuptake inhibitor and classical antidepressant, to reverse behavioral abnormalities in En2−/− mice. Desipramine treatment significantly reduced immobility in the tail suspension and forced swim tests, restored sociability in the three-chambered social approach task and reversed impairments in contextual fear conditioning in En2−/− mice. Our findings indicate that modulation of brain noradrenergic systems rescues the depression-related phenotype in En2−/− mice and suggest new roles for NE in the pathophysiology of the social and cognitive deficits seen in neuropsychiatric disorders such as autism or schizophrenia.
authors.forename: J
authors.initials: J
authors.lastname: Brielmaier
authors.forename: J M
authors.initials: JM
authors.lastname: Senerth
authors.forename: J L
authors.initials: JL
authors.lastname: Silverman
authors.forename: P G
authors.initials: PG
authors.lastname: Matteson
authors.forename: J H
authors.initials: JH
authors.lastname: Millonig
authors.forename: E
authors.initials: E
authors.lastname: DiCicco-Bloom
authors.forename: J N
authors.initials: JN
authors.lastname: Crawley
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics; D003863:Depression / Q000188:drug therapy* / Q000235:genetics; D003891:Desipramine / Q000627:therapeutic use*; D005239:Fear; D018398:Homeodomain Proteins / Q000235:genetics*; D008124:Locomotion; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012919:Social Behavior; D000099266:Engrailed 2 Protein
chemical_list: D018759:Adrenergic Uptake Inhibitors; D003891:Desipramine; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000099266:Engrailed 2 Protein
references.citation: Behav Pharmacol. 1997 Nov;8(6-7):523-32
references.pmid: 9832966
references.citation: Neuron. 2011 Dec 22;72(6):951-63
references.pmid: 22196331
references.citation: Curr Protoc Neurosci. 2011 Jul;Chapter 8:Unit 8.26
references.pmid: 21732314
references.citation: Neuropharmacology. 1989 Nov;28(11):1169-73
references.pmid: 2594162
references.citation: Arch Gen Psychiatry. 1965 Dec;13(6):483-94
references.pmid: 5320621
references.citation: Nat Protoc. 2006;1(3):1306-11
references.pmid: 17406415
references.citation: Neurosci Biobehav Rev. 2005;29(4-5):571-625
references.pmid: 15890404
references.citation: Psychopharmacol Bull. 2002 Summer;36 Suppl 2:6-23
references.pmid: 12490820
references.citation: Brain Res. 2006 Oct 20;1116(1):166-76
references.pmid: 16935268
references.citation: Am J Psychiatry. 1986 Jul;143(7):862-6
references.pmid: 3717426
references.citation: Neuropsychopharmacology. 2008 Jan;33(2):406-17
references.pmid: 17429410
references.citation: J Neurosci. 2010 Jul 28;30(30):10015-24
references.pmid: 20668186
references.citation: PLoS One. 2012;7(7):e40914
references.pmid: 22829897
references.citation: Nature. 2011 Nov 23;480(7375):63-8
references.pmid: 22113615
references.citation: Trends Genet. 1996 Jan;12(1):15-20
references.pmid: 8741855
references.citation: J Autism Dev Disord. 2000 Jun;30(3):205-23
references.pmid: 11055457
references.citation: Curr Opin Neurobiol. 1997 Apr;7(2):269-78
references.pmid: 9142760
references.citation: Behav Neurosci. 1992 Apr;106(2):274-85
references.pmid: 1590953
references.citation: Nature. 1989 Mar 9;338(6211):153-6
references.pmid: 2563902
references.citation: Nature. 2008 Oct 16;455(7215):912-8
references.pmid: 18923513
references.citation: Annu Rev Neurosci. 1979;2:113-68
references.pmid: 231924
references.citation: Mol Cell Neurosci. 2005 Jan;28(1):96-105
references.pmid: 15607945
references.citation: MMWR Surveill Summ. 2012 Mar 30;61(3):1-19
references.pmid: 22456193
references.citation: Neuropsychopharmacology. 2009 Jun;34(7):1764-73
references.pmid: 19177066
references.citation: Psychopharmacology (Berl). 2001 May;155(3):315-22
references.pmid: 11432695
references.citation: J Clin Psychiatry. 2001;62 Suppl 15:22-5
references.pmid: 11444763
references.citation: Biol Psychiatry. 2000 May 1;47(9):818-29
references.pmid: 10812041
references.citation: Am J Psychiatry. 1992 Mar;149(3):363-6
references.pmid: 1536276
references.citation: J Neurosci. 1998 Mar 1;18(5):1763-73
references.pmid: 9465001
references.citation: CNS Neurosci Ther. 2011 Dec;17(6):723-32
references.pmid: 21155988
references.citation: Psychopharmacology (Berl). 1985;85(3):367-70
references.pmid: 3923523
references.citation: Hum Mol Genet. 2012 Apr 1;21(7):1566-80
references.pmid: 22180456
references.citation: Eur Neuropsychopharmacol. 2003 Oct;13(5):355-63
references.pmid: 12957334
references.citation: J Neurosci. 1997 Oct 15;17(20):7881-9
references.pmid: 9315908
references.citation: Neuropsychopharmacology. 2004 Jul;29(7):1321-30
references.pmid: 15085085
references.citation: Arch Gen Psychiatry. 1993 Jun;50(6):441-7
references.pmid: 8498878
references.citation: Neurobiol Learn Mem. 2004 Jul;82(1):26-34
references.pmid: 15183168
references.citation: J Neurosci. 2005 Jan 5;25(1):52-61
references.pmid: 15634766
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17501-6
references.pmid: 17088541
references.citation: Mol Psychiatry. 2004 Apr;9(4):326-57
references.pmid: 14743184
references.citation: Psychol Med. 1987 May;17(2):297-309
references.pmid: 3299439