水戸 敬 国立精神, 神経センター・神経研究・疾病研究第2部, 室長 (00166068)
許斐 博史 国立精神, 神経センター・神経研究・疾病研究第2部, 室長 (00186719)
BECKER L.E. トロント大学, 小児病院・神経病理学, 教授
MITO Takashi Division of Mental Retardation and Birth Defect Research, National Institute of
BECKER L. E. Division of Neuropathology, The Hospital for Sick Children, University of Toront
KONOMI Hiroshi Division of Mental Retardation and Birth Defect Research, National Institute of
|Budget Amount *help
¥9,000,000 (Direct Cost : ¥9,000,000)
Fiscal Year 1991 : ¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1990 : ¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1989 : ¥3,000,000 (Direct Cost : ¥3,000,000)
1. Synaptic dysgenesis in neuronal migration disorders.
Neurons proliferate, migrate, settele and grow in the fetal period. Immunohistochemical and Golgi studies were performed on 6 patients with hemimegalencephaly. Immunohistochemical staining demonstrated glial, neuronal, and myelin heterotopia in the leptomeninges, cortex, white matter with glial fibrillary acidic protein, myelin basic protein, and synaptophysin antibodies. Golgi studies revealed small and deformed neurons in the superficial layers around abnormal sulci, and hypertrophic neurons with an increased number of dendrites and spines in the deeper cortex. The coexistence of a cell migration disorder, proliferation, and hypertrophy in each patient may imply a growth factor disturbance that controls cell proliferation. Immunohistochemical study on the brains with lissencephaly suggested that the sparsely cellular layer may correspond to the molecular layer and white matter in normal brain. Neurons with forming myelin sheaths
in the superficial cellular layer regularly penetrate the surface of the molecular layer, forming arrested cortical columns in the deep cellular layer. In the cases of Zellweger syndrome, G opigi studies revealed abnormal morphogenesis and delayed maturation in intrauterine development, and the imminohistochemistry suggested myelination disturbance in perinatal period.
In atypical phenylketonuria and maple syrup urine diselse there were irregular neuronal arrangement and dendritic spine reduction. This abnormalities may occur at settling of neurons, which may be influenced by metabolic disorder before birth.
2. Developmental abnormalities of catecholaminenrgic neurons in the brainstem.
The catecholaminergic neurons in the medullary dorsal and solitary nuclei of the brains tem appear to play an important role in respiratory control and those in ventrolateral medulla (VLM) in chemoreception and cardiovascular control. In immunohistochemistry of tyrosine hydroxylase (TH) and Golgi study, TH-positive neurons were identified in the VLM at 14 weeks of gestation, and the size of cell body and length of dendrites increased with maturation. In controls the number of dendritic spines increased with increasing gestational age, but decreased after 40 weeks of gestation. However, in SIDS, dendritic spines in VLM as well as in the reticular formation and vagal nuclei persisted compared to controls. Substance P-positive nervefibers were increased in the trigeminal nerve of SIDS. These observations suggest that a delay in maturation of medullary neurons in SIDS thoght to be responsible for cardiorespiratory control.
3.21 chromosome, mental retardation and precocious aging.
Dendritic soines in the cerebral cortex rapidly increase in controls, but poorly increase in childhood and more markedly decrease in elderly adults of Down syndrome. Immunohistochemistry of amyloid demonstrated early appearance of amylold deposition in plaques and vessels, which are related to precocious dementia in Down syndrome. Furthermore, we made antibodies against membrane protein which genes were coded on chromosome 21, and immunohistochemistry revealed that they appeared earlier in the temporal cortex than in the frontal cortex of Down syndrome. In addition, immunohistochemistry of S-100 showed an increase of S-100 in the temporal cortex in Down syndrome, compared with controls. This result may be related to delayed synaptic development and mental retardation. Thus, several pathogenetic factors may be related to retardation of synaptogenesis and mentality in Down syndrome.
大脳皮質の神経細胞樹状突起のスパインは出生頃から急速に増加するが,ダウン症候群では、生後の増加が少なく,シナプシスの発達遅滞があった(Brain Dev).また,シナプシスの減少も対照より早く、アミロイドの早期出現と早発痴呆と関係深いと考えられた.さらに、21番染色体コ-ドの遺伝子の特異的蛋白の抗体を作製し、免疫組織化学的に検討し、ダウン症候群の側頭葉に発現しやすいことが分かった(Develop Brain Res)。染色体21番に遺伝子があるSuperoxide dismutaseを免疫組織化学的に観察し,SODの免疫組織化学的発現は胎児中期に起こり,成人の加令では減少傾向にあった(Brain Dev).神経細胞樹状突起発達の遅れの機序を見るために,21番染色体にあるSー100を発達免疫組織化学的に検索した.Sー100は新生児と老人の側頭葉に増加し,精神遅滞との関連性が疑われた(Pediat Pathol).本症のシナプシス形成遅滞にはいくつかの因子が関与していると思われる. Less