DCC Receptors Drive Prefrontal Cortex Maturation by Determining Dopamine Axon Targeting in Adolescence.

TitleDCC Receptors Drive Prefrontal Cortex Maturation by Determining Dopamine Axon Targeting in Adolescence.
Publication TypeJournal Article
Year of Publication2017
AuthorsReynolds LM, Pokinko M, Torres-Berrío A, Cuesta S, Lambert LC, Pellitero EDel Cid, Wodzinski M, Manitt C, Krimpenfort P, Kolb B, Flores C
JournalBiol Psychiatry
Date Published2017 Jun 16
ISSN1873-2402
Abstract

BACKGROUND: Dopaminergic input to the prefrontal cortex (PFC) increases throughout adolescence and, by establishing precisely localized synapses, calibrates cognitive function. However, why and how mesocortical dopamine axon density increases across adolescence remains unknown.METHODS: We used a developmental application of axon-initiated recombination to label and track the growth of dopamine axons across adolescence in mice. We then paired this recombination with cell-specific knockdown of the netrin-1 receptor DCC to determine its role in adolescent dopamine axon growth. We then assessed how altering adolescent PFC dopamine axon growth changes the structural and functional development of the PFC by quantifying pyramidal neuron morphology and cognitive performance.RESULTS: We show, for the first time, that dopamine axons continue to grow from the striatum to the PFC during adolescence. Importantly, we discover that DCC, a guidance cue receptor, controls the extent of this protracted growth by determining where and when dopamine axons recognize their final target. When DCC-dependent adolescent targeting events are disrupted, dopamine axons continue to grow ectopically from the nucleus accumbens to the PFC and profoundly change PFC structural and functional development. This leads to alterations in cognitive processes known to be impaired across psychiatric conditions.CONCLUSIONS: The prolonged growth of dopamine axons represents an extraordinary period for experience to influence their adolescent trajectory and predispose to or protect against psychopathology. DCC receptor signaling in dopamine neurons is a molecular link where genetic and environmental factors may interact in adolescence to influence the development and function of the prefrontal cortex.

DOI10.1016/j.biopsych.2017.06.009
Alternate JournalBiol. Psychiatry
PubMed ID28720317
Grant ListF31 DA041188 / DA / NIDA NIH HHS / United States
R01 DA037911 / DA / NIDA NIH HHS / United States

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