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Updated: Jan 9, 2026
Strategies for Assessing Autistic-Like Behaviors in Mice
Published on: September 20, 2024
Mitochondrion-Mediated Metabolism and Microbiome Biodiversity Influence Autism-alike Behaviors
Yunyi Yao1, Brandon O'Sullivan2, Tapan K Mondal1
1Wadsworth Center, New York State Department of Health, Albany, USA.
Background:
The BTBR T + Itpr3tf /J (BTBR) strain has autism spectrum disorder (ASD)-like behaviors, which has been associated with mitochondrial dysfunction. Therefore, a new mouse strain was developed. The BTBR-mtB6 strain has the nuclear genome of BTBR but mitochondria from C57BL/6J (B6) mice, which have normal behaviors and immunity. The BTBR-mtB6 strain had more normal behavios and immunity. Therefore, the mechanisnisms associated with the improvements were investigated.
Aim:
Since replacement of mitochondria in BTBR mice improved behavior and some immune differences, the associated mechanisms were researched.
Methods:
Since mitochondria functions affect gut microbiota and metabolomics, the bacteria in fecal samples and metabolites in the blood and organs including the brain were investigated. Microbiome sequences were retrieved from Illumina BaseSpace. Genetic and molecular changes incuding metabolomics were assayed.
Results:
The fecal microbiomes of BTBR, B6 and BTBR-mtB6 mice were different from each other. The serum and brain cholesterol levels were intermediate between males of the BTBR and B6 strain. The liver PPARγ level also was intermediate between the BTBR and B6 strain which may relate to the BTBR-mtB6 intermediate amount of lipid in the liver. The BTBR-mtB6 mice also had an intermediate number of T cells in the white adipose tissue compared to the BTBR and B6 mice. Complex IV of the ETC in the liver was slightly lower in the BTBR-mtB6 mice than B6 mice. The BTBR-mtB6 strain lost production of IgG to brain antigen that is observed in BTBR mice.
Conclusion:
The mitochondrial shift is shown to affect fecal microbiota, mitochondrion-dependent metabolism affecting lipid accumulation, the levels of cholesterol in the brain and serum, and brain expression of myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), which improves myelination in BTBR-mtB6 brains. The metabolite and microbiome differences likely relate to mitochondrial/nuclear differences affecting metabolism, immunity, and behavior.
Insights
Mitochondrial DNA transfer improved autism spectrum disorder (ASD)-like behaviors in BTBR mice by altering gut microbiota and brain cholesterol. This highlights the role of mitochondria in neurodevelopment and immunity.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- BTBR mice exhibit autism spectrum disorder (ASD)-like behaviors linked to mitochondrial dysfunction.
- A novel mouse model, BTBR-mtB6, was created using BTBR nuclear DNA and C57BL/6J (B6) mitochondria, which possess normal behavior and immunity.
- The BTBR-mtB6 strain displayed normalized behaviors and immune profiles compared to BTBR mice.
Purpose of the Study:
- To investigate the mechanisms underlying the behavioral and immunological improvements in BTBR-mtB6 mice.
- To explore the impact of mitochondrial replacement on gut microbiota, metabolomics, and associated physiological changes.
Main Methods:
- Analysis of fecal microbiome composition using sequencing.
- Assay of genetic and molecular changes, including metabolomics in blood and organs (brain, liver).
- Evaluation of immune cell populations (T cells) and protein levels (PPARγ, Complex IV, IgG).
Main Results:
- Distinct fecal microbiome profiles were observed across BTBR, B6, and BTBR-mtB6 strains.
- Serum and brain cholesterol levels in BTBR-mtB6 mice were intermediate between BTBR and B6 mice.
- Liver PPARγ levels and white adipose tissue T cell counts were intermediate, suggesting altered lipid metabolism and immune responses.
Conclusions:
- Mitochondrial DNA replacement influences fecal microbiota, metabolism, and brain myelination (MBP, CNPase expression).
- Metabolite and microbiome alterations in BTBR-mtB6 mice are linked to mitochondrial-nuclear interactions affecting metabolism, immunity, and behavior.
- These findings underscore the critical role of mitochondria in modulating complex phenotypes relevant to ASD.
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