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Neuropsychopharmacology. 2019 Mar;44(4):703-710. doi: 10.1038/s41386-018-0189-3. Epub 2018 Aug 27.

Interactive effects between hemizygous 15q13.3 microdeletion and peripubertal stress on adult behavioral functions.

Author information

1
Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
2
Cereneo Center for Interdisciplinary Research, Vitznau, Switzerland.
3
Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark.
4
Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
5
iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
6
National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
7
Centre for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark.
8
Neuroscience, Lundbeck A/S, Valby, Denmark.
9
Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland. urs.meyer@vetpharm.uzh.ch.
10
Neuroscience Centre Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland. urs.meyer@vetpharm.uzh.ch.

Abstract

15q13.3 microdeletion is one of several gene copy number variants (CNVs) conferring increased risk of psychiatric and neurological disorders. This microdeletion gives rise to a variable spectrum of pathological phenotypes, ranging from asymptomatic to severe clinical outcomes. The reasons for these varying phenotypic outcomes remain unknown. Using a mouse model of hemizygous deletion of the orthologous region of 15q13.3, the present study examined whether exposure to stressful life events might interact with hemizygous 15q13.3 microdeletion in the development of behavioral dysfunctions. We show that hemizygous 15q13.3 microdeletion alone induces only limited effects on adult behaviors, but when combined with psychological stress in pubescence (postnatal days 30-40), it impairs sensorimotor gating and increases the sensitivity to the psychostimulant drug, amphetamine, at adult age. Stress exposure in adolescence (postnatal days 50-60) did not induce similar interactions with 15q13.3 microdeletion, but led to impaired emotional learning and memory and social behavior regardless of the genetic background. The present study provides the first evidence for interactive effects between hemizygous 15q13.3 microdeletion and exposure to stressful life events, and at the same time, it emphasizes an important influence of the precise timing of postnatal stress exposure in these interactions. Our findings suggest that hemizygous 15q13.3 microdeletion can act as a "disease primer" that increases the carrier's vulnerability to the detrimental effects of peripubertal stress exposure on adult behaviors.

PMID:
30188511
PMCID:
PMC6372643
[Available on 2020-03-01]
DOI:
10.1038/s41386-018-0189-3

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