title: dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients.
abstract: Adolescence is a period of heightened susceptibility to psychiatric disorders of medial prefrontal cortex (mPFC) dysfunction and cognitive impairment. mPFC dopamine (DA) projections reach maturity only in early adulthood, when their control over cognition becomes fully functional. The mechanisms governing this protracted and unique development are unknown. Here we identify dcc as the first DA neuron gene to regulate mPFC connectivity during adolescence and dissect the mechanisms involved. Reduction or loss of dcc from DA neurons by Cre-lox recombination increased mPFC DA innervation. Underlying this was the presence of ectopic DA fibers that normally innervate non-cortical targets. Altered DA input changed the anatomy and electrophysiology of mPFC circuits, leading to enhanced cognitive flexibility. All phenotypes only emerged in adulthood. Using viral Cre, we demonstrated that dcc organizes mPFC wiring specifically during adolescence. Variations in DCC may determine differential predisposition to mPFC disorders in humans. Indeed, DCC expression is elevated in brains of antidepressant-free subjects who committed suicide.
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Manitt
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Pokinko
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: R T
authors.initials: RT
authors.lastname: Ryan
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Torres-Berrío
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: J P
authors.initials: JP
authors.lastname: Lopez
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: S V
authors.initials: SV
authors.lastname: Yogendran
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: M J J
authors.initials: MJ
authors.lastname: Daubaras
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Grant
authors.affiliation: Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E R E
authors.initials: ER
authors.lastname: Schmidt
authors.affiliation: UMR 7224 CNRS and Université Pierre et Marie Curie, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Tronche
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, Cancer Genomics Centre, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Krimpenfort
authors.affiliation: The University of Queensland, Queensland Brain Institute, Brisbane, QLD, Australia.
authors.forename: H M
authors.initials: HM
authors.lastname: Cooper
authors.affiliation: Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: R J
authors.initials: RJ
authors.lastname: Pasterkamp
authors.affiliation: Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Kolb
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Turecki
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: T P
authors.initials: TP
authors.lastname: Wong
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: 1] Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada [2] UMR 7224 CNRS and Université Pierre et Marie Curie, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Giros
authors.affiliation: Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Flores
mesh_terms: D000293:Adolescent; D041923:Adolescent Development / Q000502:physiology; D000818:Animals; D016022:Case-Control Studies; D059290:Dopaminergic Neurons / Q000378:metabolism*; D016163:Genes, DCC / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D051379:Mice; D009434:Neural Pathways / Q000254:growth & development / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D016728:Self-Injurious Behavior / Q000235:genetics; D013405:Suicide