Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system

Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system

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J Psychiatry Neurosci 2011;36(5):296-310

Cecilia Flores, PhD

Department of Psychiatry, McGill University, Douglas Hospital Research Centre, Montréal, Que.

Abstract

Changes in mesocorticolimbic dopamine (DA) neurons and their target cells can be induced throughout life and are important determinants of individual differences in susceptibility to psychopathology. The goal of my research is to gain insight into the nature of the cellular and molecular mechanism underlying the selective plasticity of mesocorticolimbic DA neurons. Here, I review work showing that the guidance cue netrin-1 is implicated in the organization, plasticity and function of mesocorticolimbic DA neurons in rodents. Developmental variations in netrin-1 receptor function result in selective reorganization of medial prefrontal DA circuitry during adolescence and in an adult phenotype protected against schizophrenia-like dopaminergic and behavioural abnormalities. Furthermore, in adulthood, expression of netrin-1 receptors is upregulated by repeated exposure to stimulant drugs of abuse in DA somatodendritic regions and is necessary for drug-induced behavioural plasticity. I propose that risk factors associated with DA-related adult psychiatric disorders alter netrin-1 function.


Submitted Dec. 2, 2010; Revised Jan. 29, 2011; Accepted Feb. 3, 2011.

Acknowledgments: This work was supported by the Canadian Institutes of Health Research (MOP-74709), the Natural Sciences and Engineering Research Council of Canada and salary awards from the Fonds de la recherche en santé du Québec. The work was accomplished as a result of the efforts of current and former lab members, primarily 2 current doctorate students, Alanna Grant and Leora Yetnikoff, and both a former and a current postdoctoral fellow, Cassandre Labelle-Dumais and Colleen Manitt, respectively. I thank Jane Stewart not only for her comments and suggestions on this manuscript, but also for all her support and guidance throughout my career. I also thank my collaborators Andreas Arvanitogiannis and Bryan Kolb, who have made essential contributions to the work reviewed here.

Competing interests: None declared.

DOI: 10.1503/jpn.100171

Correspondence to: Dr. C. Flores, Department of Psychiatry, McGill University, Douglas Hospital Research Centre, 6875 LaSalle Blvd., Montréal QC H4H 1R3; cecilia.flores@mcgill.ca