Environmental and genetic correlates of neuropsychiatric diseases and the role of erythropoietin/hypoxia in the brain as potential treatment targets
by Agnes Steixner-Kumar née Steixner
Date of Examination:2021-06-07
Date of issue:2021-06-15
Advisor:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Susann Boretius
Persistent Address:
http://dx.doi.org/10.53846/goediss-8661
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Abstract
English
Neuropsychiatric disorders are relatively frequent and present a considerable burden to affected individuals and society. Disease etiology is often complex and patients exhibit large heterogeneity regarding disease causing factors, presentation and progression. Available treatment options are often ineffective and/or linked to unwanted side-effects. On the other hand, availability of successful preventive actions is limited and requires a detailed study of risk factors for neuropsychiatric disease and its specific symptoms. The first part of this thesis aimed to investigate environmental and genetic risk factors for polytoxicomania, i.e. multiple drug (ab)use, as a frequent comorbidity of schizophrenia. In a sample of $\sim$2000 schizophrenia/schizoaffective patients, we addressed the question if the exposure to accumulated environmental risk in early life increases susceptibility to polytoxicomania. Indeed, the accumulation of environmental risk was strongly associated with polytoxicomania throughout life and in particular in pre-adulthood. Moreover, the development of a novel GWAS-PGAS approach led to the identification of 41 common genetic variants potentially conferring risk to preadult polytoxicomania. The objective of the second part of this thesis work was to further investigate brain-directed effects of hypoxia and erythropoietin (EPO) - a central hypoxia-inducible gene - as potential treatment option for neuropsychiatric disorders. Using a hypoxia reporter mouse line (CAG-CreERT2-ODD::R26R-tdTomato), we showed that both inspiratory hypoxia and motor-cognitive challenge, which causes endogenous hypoxia as a result of extensive neuronal activation (termed "functional hypoxia"), increased the number of hypoxic cells in the brain and the expression of hypoxia-inducible genes in the hippocampus. Interestingly, cell types showed variable responsivity to hypoxia: While neurons and endothelial cells were frequently labelled, hypoxia-labelling in microglia was entirely absent. Technical artifacts explaining this phenomenon were excluded by comparing construct mRNA levels across all cell types. Hexokinase 2 (Hk2) was identified as a mediator of cell type-specific hypoxia responsivity. In addition, we report rapid effects of EPO on adult neurodifferentiation in the CA1 (6 hours after injection). Enhanced neuronal differentiation continued under EPO treatment, driving immature neurons (\textit{Tbr1}+, \textit{Tle4}+ and later \textit{Zbtb20}+) towards maturity, and resulted in $\sim$20\% more neurons in the CA1 after 3 weeks of treatment. Simultaneously, the number of microglia in this region declined by an initial wave of apoptosis, followed by attenuated proliferation. This reduction was necessary for the increase in new neurons. Expression data further indicated that the microglial-neuron balance was maintained by signalling of microglial Colony-Stimulating Factor 1 Receptor (CSF1R) and its neuronally expressed ligand Interleukin 34 (IL34).
Keywords: Neuropsychiatric disease; Schizophrenia; Polytoxicomania; Multiple drug abuse; Hypoxia; Erythropoietin; Neurodifferentiation; Microglia; Hippocampus
