ミトコンドリアＤＮＡがシナプス発達に関与するしくみ

2015 Fiscal Year Annual Research Report

• Project/Area Number: 15F15105
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: 内匠 透 国立研究開発法人理化学研究所, 脳科学総合研究センター, シニアチームリーダー (00222092)
• Co-Investigator(Kenkyū-buntansha): LIN CHIA WEN 国立研究開発法人理化学研究所, 脳科学総合研究センター, 外国人特別研究員
• Project Period (FY): 2015-04-24 – 2017-03-31
• Keywords: 炎症 / 自閉症

Outline of Annual Research Achievements

Neuroinflammation is observed in autistic brain. However, the mechanism of the pathologic meaning remains unknown. Our study suggests both BTBR mice from both JAX and Riken BRC recapitulate the neuroinflammation phenotype observed in human autistic brain. BTBR is the model to investigate the pathogenesis of neuroninflammation.

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

Inflammatory cytokines, IL-6 and TNF-α are increased in BTBR brains from early embryonic brain, E12, to early postnatal day 5. As the brain matures, increased inflammatory cytokines are limited to cerebellum. The spine density in the purkinje cell is found to be increased in BTBR. It is proposed that the inflammatory environment in early developmental stages will lead to hyper-connectivity in local brain regions. Primary culture of microglia, astrocyte and neuron are established to clarify which cell type is responsible for the inflammation in brain. The result suggests only microglia from BTBR shows similar change in the cytokine profiles as observed in the brain. Furthermore, PU.1, the transcription factor involving in microglia differentiation/activation, is increased in BTBR microglia. This suggests the abnormal microglia development. In addition to inflammation in brain, we also find that cytokine expression is changed in BTBR colon. Microglia and peripheral immune cells are differentiated from hematopoietic stem cells (HSC) in yolk sac and aorta-gonad mesonephros (AGM), respectively, during embryonic stage. After birth, HSC are mainly located in bone marrow. To investigate whether pathologic HSC causes impaired development of immune cells and leads to aberrant cytokine expression, B6 were exposed to sublethal dose of total body irradiation and received bone marrow from BTBR mice. The preliminary result shows the recipient B6 can partially recapitulate the inflammatory phenotypes observed in BTBR.

Strategy for Future Research Activity

1. To confirm the hyper connectivity in BTBR neuron by electrophysiology
2. To investigate which types of immune cell mediate the cytokine change in the colon.
3. To analyze the gene expression profiles in HSC by RNA-seq.
4. To rescue BTBR inflammatory phenotype by transplanting B6 bone marrow cells.