Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

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J Psychiatry Neurosci 2016;41(3):169-181

Elsa Isingrini, PhD; Lea Perret, MSc; Quentin Rainer, PhD; Sara Sagueby, MSc; Luc Moquin, MSc; Alain Gratton, PhD; Bruno Giros, PhD

Abstract

Background: The monoaminergic transmitters dopamine (DA), noradrenaline (NE) and serotonin (5-HT) modulate cerebral functions via their extensive effects in the brain. Investigating their roles has led to the creation of vesicular monoaminergic transporter-2 (VMAT2) knockout (KO) mice. While this mutation results in postnatal death, VMAT2-heterozygous (HET) mice are viable and show a complex behavioural phenotype. However, the simultaneous alteration of the 3 systems prevents investigations into their individual functions.

Methods: To assess the specific role of NE, 5-HT and DA, we genetically disrupted their neurotransmission by creating conditional VMAT2-KO mice with targeted recombination. These specific recombinations were obtained by breeding VMAT2lox/lox mice with DBHcre, SERTcre and DATcre mice, respectively. We conducted a complete neurochemical and behavioural characterization of VMAT2-HET animals in each system.

Results: Conditional VMAT2-KO mice revealed an absence of VMAT2 expression, and a specific decrease in the whole brain levels of each monoamine. Although NE- and 5-HT-depleted mice are viable into adulthood, DA depletion results in postnatal death before weaning. Interestingly, alteration of the DA transmission fully accounted for the increased amphetamine response formerly observed in the VMAT2-HET mice, whereas alteration of the 5-HT system was solely responsible for the increase in cocaine response.

Limitations: We used VMAT2-HET mice that displayed a mild phenotype. Because the VMAT2-KO in DA neurons is lethal, it precluded a straightforward comparison of the full KOs in the 3 systems.

Conclusion: Given the intermingled functions of NE, 5-HT and DA in regulating cognitive and affective functions, this model will enhance understanding of their respective roles in the pathophysiology of psychiatric disorders.


Submitted Jan. 29, 2015; Revised June 25, 2015; Accepted July 13, 2015; Early-released Oct. 27, 2015

Acknowledgements: This work was supported by the Canada Research Chairs program, the Canadian Foundation for Innovation, the Graham Boeckh Foundation for Schizophrenia Research and by NSERC RGPIN 385732-2012 to B. Giros. E. Isingrini is supported by a postdoctoral grant from the Fonds de recherche du Québec – Santé. B. Giros is a Canadian Research Chair in Neurobiology of Mental Disorders. The authors thank Erika Vigneault and Marie-Eve Desaulniers for excellent care and maintenance of all mice colonies and François Tronche for the DAT Cre mice.

Affiliations: From the Department of Psychiatry, Douglas Mental Health research center, McGill University, Montreal, Que., Canada (Isingrini, Perret, Rainer, Sagueby, Moquin, Gratton, Giros); and ISERM, UMRS 1130; CNRS, UMR 8246; Sorbonne University UPMC, Neuroscience Paris-Seine, F-75005, Paris, France (Giros).

Competing interests: None declared.

Comtributors: E. Isingrini and B. Giros designed the study. E. Isingrini, L. Perret, Q. Rainer, S. Sagheby, L. Moquin and A. Gratton acquired the data, which E. Isingrini, L. Perret, L. Moquin, A. Gratton and B. Giros analyzed. E. Isingrini and B. Giros wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.150028

Correspondence to: B. Giros, Douglas Hospital Research Centre, McGill University, 6875 Boul LaSalle, Montreal, Que.; Bruno.giros@mcgill.ca