Down Syndrome, Neurodevelopment And Neurodegeneration

Aging

Investigators

Linked publications & trials

Abstract

(1) Cultured neurons from fetuses of animal models for Down syndrome (DS), the full trisomy 16 (Ts16) and partial trisomy 16 (Ts65Dn) mice, demonstrate abnormal electrical and biochemical properties which are comparable to those found in fetal neurons from human trisomy 21 DS fetuses. The hippocampus from the Ts65Dn mouse demonstrates abnormal long-term potentiation and depression, thus disturbed synaptic plasticity. Mental retardation in DS was postulated to be related to disturbed neuronal electrical properties and neuroplasticity that have been described in fetal mouse and human cultured neurons by our laboratory. (2) The gene encoding the NR2A subunit of the NMDA receptor is on mouse chromosome 16, syntetic with human chromosome 21. Its expression is increased 2.5-fold in cultured Ts16 embryonic hippocampal neurons, but their NMDA-evoked currents are not altered. (3) We reported that myoinositol is abnormally elevated in the human DS brain and cerebrospinal fluid, in the brain of the Ts65Dn mouse model for DS, and in the brain of Alzheimer disease patients. Thus, we proposed that elevated brain myoinositol is accompanied by altered turnover of the phosphatidylinositide cycle, which critical in neuronal signal transduction. (4) A method was developed to measure phosphatidylinositide turnover in cultured cortical neurons, using deuterated myoinositol with mass spectrometry. Half-lives of 10 hours for phosphatidylinositol were estimated from the measurements. (5) Continuous cell lines were established from spinal cord and dorsal root ganglia of normal and trisomy 16 fetal mice. The trisomic cell lines overexpressed traits also overexpressed in the human DS brain and fetal human and trisomic mouse neurons, including the mRNA for Cu/Zn superoxide dismutase, and abnormal electrical signaling and responses to cholinergic drugs. These cells can be used to understand the basis of mental retardation in DS.