Genetics of stress-induced aggression in mice

Anna Gorlova
About the Author

Anna Gorlova is an external PhD student at Maastricht University (the Netherlands) and visiting trainee at Liege University (Belgium), appointed in the Sechenov First Moscow State Medical University (Russia). She studies the molecular mechanisms of excessive aggression and explores new pharmacological management in different mouse models.


Background

The contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2−/−) are naturally highly aggressive, while heterozygous mice (Tph2+/−) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically ‘susceptible’ heterozygous mice (Tph2+/−).

Methods

Tph2+/− male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied.

Results

Stressed Tph2+/− mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/− mice.

Limitations

Rescue experiments would help to verify causal relationships of reported changes.

Conclusions

The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes.


Publication information

Title: Stress-induced aggression in heterozygous TPH2 mutant mice is associated with alterations in serotonin turnover and expression of 5-HT6 and AMPA subunit 2A receptors

Authors:  Anna Gorlova, Gabriela Ortega, Jonas Waider, Natalia Bazhenova, Ekaterina Veniaminova, Andrey Proshin, Allan V. Kalueff, Daniel C. Anthony, Klaus-Peter Lesch, Tatyana Strekalova

Journal: Journal of Affective Disorders;

Year: 2020

Url: https://doi.org/10.1016/j.jad.2020.04.014