Institutional creator:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Contributor:

Adamczyk, Agata (Promotor) ; Cieślik, Magdalena (Promotor pomocniczy)

Publisher:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Place of publishing:

Warszawa

Degree name:

doktor

Level of degree:

2

Degree discipline :

medical sciences

Degree grantor:

Mossakowski Medical Research Institute Polish Academy of Sciences

Abstract:

Autism spectrum disorders (ASD) are a diverse group of neurodevelopmental disorders, Leading theory states that ASD occurs as a result of influence of both genetic and environmental factors, including prenatal stress, such as maternal immune activation (MIA) during pregnancy, what was confirmed by epidemiological studies. Moreover, animals prenatally exposed to MIA show ASD-like behaviors later in life. Up until now, no research would focus of mitochondrial functioning in the brain of MIA offspring, even though mitochondrial dysfunction has been diagnosed in ASD patients. Therefore, the aim of this research was to test the hypothesis that mitochondrial dysfunction occurs in ASD caused by maternal immune activation. In this research, animal model of MIA was induced by injection of lipopolysaccharide (LPS, 100 µg/kg b.w.) to pregnant Wistar rat at day 9.5 of pregnancy. Experiments were conducted using immunochemical, luminescent, spectrophotometric, spectrofluorimetric and microscopic methods. Behavioral tests were also performed. Is was showed that LPS injection causes increase in expression of Il1b, Il6, Ifng and Tnf, NADPH oxidase (NOX) activation and increase in reactive oxygen species (ROS) in fetal tissue. Moreover, decreased mitochondrial membrane potential and ATP levels were observed. Behavioral tests revealed ASD-like changes in behavior. Infants at 10-11 postnatal vocalized less when isolated form family, and at postnatal day 15, MIA offspring showed less interest in home odor. Young adults (postnatal day 50) showed decreased sociability and decreased interest in social novelty. Expression of Il1b and Ifng was increased in the brain of infants prenatally exposed to MIA. At the same time, increased activity of NOX and high levels of ROS were observed. Additionally, decreased mitochondrial membrane potential and ATP levels were observed, even though there were no changes in activity or expression of mitochondrial electron transport chain. Moreover, despite observed changes in mitochondrial membrane potential, there was no difference in mitochondria content or levels of proteins involved in PINK1/parkin-dependent mitophagy. Finally, increased expression of genes for mitochondrial dynamics and biogenesis suggests some compensation mechanism, in response to cellular stress. Increased expression of Il6, Tnf, Ptgs2 and Alox12 was demonstrated in cerebral cortex of MIA animals, which was accompanied by microglia activation. Such effect was not observed in hippocampus. Both structures showed increased ROS levels, and decreased GSH/GSSG ratio. However, only in hippocampus high activity of NOX was observed. It seems that mitochondria are disturbed at this time point in a structure-dependent matter. In cerebral cortex both expression and activity of three mitochondrial complexes (CI (mt-Nd1), CIII (mt-Cyb) and CIV(mt-Co1)) were decreased, whereas in hippocampus decreased expression of mt-Nd1 and mt-Co1 and activity of CI and CIII were observed. Moreover, it was demonstrated that mitochondrial membrane potential and ATP levels decreased in both structures, and in cerebral cortex fragmentation was increased, with no change in mitophagy. Finally, analysis with transmission electron microscopy revealed many changes in mitochondrial ultrastructure, including blurred cristae and mitochondrial membrane, and signs of mitochondrial swelling, in both structures. To conclude, obtained results indicate that activation of the maternal immune system during pregnancy causes disturbance in mitochondrial functioning and ultrastructure in brain of the offspring, in an age-dependent and structure-dependent manner. It seems that mitochondria might be an attractive target for potential therapeutical intervention in ASD induced by maternal immune activation during pregnancy.

Detailed Resource Type:

PhD Dissertations

Format:

pdf

Resource Identifier:

oai:rcin.org.pl:240105

Source:

IMDiK PAN, sygn. ZS 428 ; click here to follow the link

Language:

pol

Language of abstract:

eng

Rights:

Creative Commons Attribution BY 4.0 license

Terms of use:

Copyright-protected material. [CC BY 4.0] May be used within the scope specified in Creative Commons Attribution BY 4.0 license, full text available at: ; -

Digitizing institution:

Mossakowski Medical Research Institute PAS

Original in:

Library of the Mossakowski Medical Research Institute PAS

Projects co-financed by:

Operational Program Digital Poland, 2014-2020, Measure 2.3: Digital accessibility and usefulness of public sector information; funds from the European Regional Development Fund and national co-financing from the state budget.

Access:

Open