Investigating the impact of cellular senescence of neuronal progenitor cells and microglia on cellular functionality and behavior
Biological Psychiatry
Final Report Abstract
In the past four years we could show, that male and female microglia differ in their mRNA and protein profile. With regard to the proposal, we found that the male microglia might enter a senescent state earlier than female microglia due to a higher activation state. Female microglia express more factors that protect against cellular damage. The sexual dimorphism in microglia cellular phenotype and function might be one of the underlying factors why some psychiatric and neurological diseases have different prevalence in both genders. Thanks to the support by the DFG we were able to be one of the first scientific groups (and to our knowledge the first group in Germany) investigating sexual dimorphism in microglia. Indeed, we found in our prenatal stress model that only male microglia respond to the stressor with telomere shortening, while female microglia seem to be protected. Moreover, we learned that changes in microglia induced in utero (priming) are reversible in the adult by several treatment strategies. Our data support ongoing clinical trials for add on treatments of patients suffering from schizophrenia. We were able to produce the first transcriptomic analysis of hippocampal microglia derived from a murine model of schizophrenia with and without treatment. These data will set basis for further studies aiming at using microglia as a therapeutic target in schizophrenia and other psychiatric diseases. In addition, we could show that upon administration of prenatal stressors increased telomere shortening is high and persistent until the adulthood. Thus, telomere dynamics are susceptible to harmful external factors during intrauterine life. Telomere length in hippocampus highly correlates with the telomere length in PBMCs and spleen. Therefore, measurement of telomere length in actively proliferating peripheral cells constitutes a good indicator for hippocampal telomere attrition. We actually came across the sexual dimorphism in microglia while starting our investigation on telomere length in the different models by chance. This was not very surprising knowing the literature about sexual dimorphism in the brain and the immune system. However, we were actually one of the first groups investigating sexual dimorphism in the immune cells of the brain – the microglia. One might see it as a downside that we had to diverge from the proposal to show this phenomenon under physiological conditions first. In addition, investigating both sexes increases the amount of time (and money) we will have to spend to conclude the studies. On the other hand, I believe that this is one great example how science is moving forward: carefully observing the data open minded not restricted by expectations and prejudices.
Publications
- Deep brain stimulation during early adolescence prevents microglial alterations in a model of maternal immune activation. Brain Behavior and Immunity, 2016 Dec 7
Ravit Hadar, Le Dong, Lucia del-Valle-Antón, Dilansu Guneykaya, Mareike Voget, Henriette Edemann-Callesen, Regina Schweibold, Anais Djodari-Irani, Thomas Götz, Samuel Ewing, Helmut Kettenmann, Susanne A. Wolf, Christine Winter
(See online at https://doi.org/10.1016/j.bbi.2016.12.003) - Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment. Translational Psychiatry (2017) 7, e1120
Mattei D, Ivanov A, Ferrai C, Jordan P, Guneykaya D, Buonfiglioli A, Schaafsma W, Przanowski P, Deuther-Conrad W, Brust P, Hesse S, Patt M, Sabri O, Ross TL, Eggen BJL, Boddeke EWGM, Kaminska B, Beule D, Pombo A, Kettenmann H and Wolf SA
(See online at https://doi.org/10.1038/tp.2017.80) - Transcriptional and Translational Differences of Microglia from Male and Female Brains. Cell Rep. 2018 Sep 4;24(10):2773-2783.e6
Guneykaya D, Ivanov A, Hernandez DP, Haage V, Wojtas B, Meyer N, Maricos M, Jordan P, Buonfiglioli A, Gielniewski B, Ochocka N, Cömert C, Friedrich C, Artiles LS, Kaminska B, Mertins P, Beule D, Kettenmann H, Wolf SA
(See online at https://doi.org/10.1016/j.celrep.2018.08.001)
