MITO Takashi Division of Mental Retardation and Birth Defect Research, National Institute of, 神経センター・神経研究・疾病研究第2部, 室長 (00166068)
KONOMI Hiroshi Division of Mental Retardation and Birth Defect Research, National Institute of, 神経センター・神経研究・疾病研究第2部, 室長 (00186719)
BECKER L. E. Division of Neuropathology, The Hospital for Sick Children, University of Toront, 小児病院・神経病理学, 教授
|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. Less