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Transl Psychiatry. 2013 Dec 17;3:e338. doi: 10.1038/tp.2013.105.

dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients.

Author information

1
Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
2
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
3
UMR 7224 CNRS and Université Pierre et Marie Curie, Paris, France.
4
Division of Molecular Genetics, Centre for Biomedical Genetics, Cancer Genomics Centre, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
5
The University of Queensland, Queensland Brain Institute, Brisbane, QLD, Australia.
6
Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB, Canada.
7
Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA.
8
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.

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.

PMID:
24346136
PMCID:
PMC4030324
DOI:
10.1038/tp.2013.105
[Indexed for MEDLINE]
Free PMC Article
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