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Longitudinal Diffusion Tensor Imaging Revealed Nerve Fiber Alterations in Aspm Mutated Microcephaly Model Mice
Hiroshi Ogi1, Nobuhiro Nitta2, So Tando1
1Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (KPUM), Kyoto 602-8566, Japan.
Neuroscience
|December 19, 2017
Summary
This study used abnormal spindle-like, microcephaly-associated (ASPM) gene knockout mice to investigate microcephaly. MRI and histopathology revealed impaired brain development, with lower fractional anisotropy (FA) values and abnormal neurite outgrowth in knockout mice.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Autosomal recessive primary microcephaly-5 (MCPH5) is a congenital condition characterized by a small brain, caused by mutations in the abnormal spindle-like, microcephaly-associated (ASPM) gene.
- Understanding the underlying mechanisms of MCPH5 is crucial for developing diagnostic and therapeutic strategies.
Purpose of the Study:
- To evaluate postnatal brain development in a mouse model of MCPH5, specifically using Aspm knockout (KO) mice.
- To correlate radiological findings from in vivo MRI with histopathological analyses.
- To investigate the relationship between fractional anisotropy (FA) changes and cellular pathology in the developing brain.
Main Methods:
- In vivo magnetic resonance imaging (MRI) was performed on Aspm KO mice and control littermates at postnatal 3 weeks (P3W) and 10 weeks (P10W).
- Histopathological analyses, including neurite outgrowth assessment and myelin basic protein staining, were conducted at postnatal 5 weeks (P5W) and 13 weeks (P13W).
- Voxel-based statistics were used to analyze MRI data, focusing on brain size, ventricular volume, and fractional anisotropy (FA) values.
Main Results:
- Aspm KO mice exhibited significantly reduced brain sizes and enlarged ventricles compared to controls at both MRI time points.
- Lower FA values were observed in the cortex and white matter of Aspm KO mice, indicating altered white matter integrity.
- Histometric analyses revealed abnormal neurite outgrowth ratios in cortical layers and decreased myelin basic protein expression in the white matter of Aspm KO mice, particularly at later time points.
Conclusions:
- The study demonstrates a strong correlation between temporal FA changes detected by MRI and pathological findings such as abnormal neurite outgrowth and myelination deficits in Aspm KO mice.
- These findings suggest that MRI-based FA analysis can be a valuable tool for assessing brain development in MCPH5 models.
- The results provide insights into the pathological mechanisms of microcephaly associated with ASPM mutations and may inform the analysis of diseased human brain development.
