Establishment and Characterization of a Gnotobiotic Mouse Model with Relevance to Infection-Mediated Neurodevelopmental Disorders
Final Report Abstract
Prenatal exposure to infection or inflammatory conditions is increasingly recognized to play an important etiological role in neuropsychiatric and neurological disorders with neurodevelopmental components. Immune-related early life adversities can also negatively affect various physiological functions beyond those typically associated with brain development. It has recently been shown that prenatal infection leads to dysbiosis of the gut microbiota and associated gastrointestinal abnormalities. Since the gut microbiota appears to have an important role in normal brain development and maturation, microbial dysbiosis during critical developmental periods may contribute to the subsequent emergence of behavioral abnormalities typically seen in subjects with prenatal infectious histories. Direct evidence for this hypothesis, however, is lacking. Against these backgrounds, the main objective of the proposed research was to examine whether dysbiosis of the gut microbiota induced by prenatal infection functionally contributes to the subsequent emergence of behavioral and neuronal deficits. In order to test this, we planned to use a novel gnotobiotic mouse model that selectively mimics a prenatal infection-mediated dysbiosis of gut microbiota. In this model, germ-free female mice were to be colonized with microbial communities obtained from mice that were initially exposed to prenatal viral-like infection or to prenatal control treatment. These gnotobiotic recipient mice were then to be mated with germ-free males to obtain gnotobiotic offspring, which either display a dysbiosis of the gut microbiota or harbor a control gut microbiota. Due to problems with the isolators at the Gnotobiotic Unit of the University of Zurich during the time of the establishment of the model we were not able to successfully colonize germ-free female mice and mate them with germ-free males (Objective 2 and 3). However, we were able to successfully generate direct descendants of gestationally infected or non-infected mothers (Objective 1) and confirm the previously observed dysbiosis of gut microbiota together with the expected behavioral deficits (social interaction deficit). Furthermore, we have extended this line of research focusing on the transgenerational transmission up to the third generation of both behavioral deficits and changes in microbial composition. We found that a) social interaction deficits were transmitted up to the third generation, b) behavioral despair – a measure for depressive-like behavior – only appeared as of the second generation and was subsequently transmitted to the third generation, c) that changes in the relative abundance of gut bacteria differed across generations and that d) prenatal treatment affected the composition of gut microbiome across generations.
Publications
- (2017): You need guts to make new neurons. Current Behavioral Neuroscience Reports
Wolf AS, Mattei D
(See online at https://doi.org/10.1007/s40473-017-0127-4) - (2019): Basic Concept of Microglia Biology and Neuroinflammation in Relation to Psychiatry. Neuroinflammation and Schizophrenia (Current Topics in Behavioral Neurosciences., Springer)
Notter T and Mattei D
(See online at https://doi.org/10.1007/7854_2018_83)
