title: On the cause of mental retardation in Down syndrome: extrapolation from full and segmental trisomy 16 mouse models.
abstract: Down syndrome (DS, trisomy 21, Ts21) is the most common known cause of mental retardation. In vivo structural brain imaging in young DS adults, and post-mortem studies, indicate a normal brain size after correction for height, and the absence of neuropathology. Functional imaging with positron emission tomography (PET) shows normal brain glucose metabolism, but fewer significant correlations between metabolic rates in different brain regions than in controls, suggesting reduced functional connections between brain circuit elements. Cultured neurons from Ts21 fetuses and from fetuses of an animal model for DS, the trisomy 16 (Ts16) mouse, do not differ from controls with regard to passive electrical membrane properties, including resting potential and membrane resistance. On the other hand, the trisomic neurons demonstrate abnormal active electrical and biochemical properties (duration of action potential and its rates of depolarization and repolarization, altered kinetics of active Na(+), Ca(2+) and K(+) currents, altered membrane densities of Na(+) and Ca(2+) channels). Another animal model, the adult segmental trisomy 16 mouse (Ts65Dn), demonstrates reduced long-term potentiation and increased long-term depression (models for learning and memory related to synaptic plasticity) in the CA1 region of the hippocampus. Evidence suggests that the abnormalities in the trisomy mouse models are related to defective signal transduction pathways involving the phosphoinositide cycle, protein kinase A and protein kinase C. The phenotypes of DS and its mouse models do not involve abnormal gene products due to mutations or deletions, but result from altered expression of genes on human chromosome 21 or mouse chromosome 16, respectively. To the extent that the defects in signal transduction and in active electrical properties, including synaptic plasticity, that are found in the Ts16 and Ts65Dn mouse models, are found in the brain of DS subjects, we postulate that mental retardation in DS results from such abnormalities. Changes in timing and synaptic interaction between neurons during development can lead to less than optimal functioning of neural circuitry and signaling then and in later life.
authors.affiliation: Section on Brain Physiology and Metabolism, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. zgalszicki@usuhs.mil
authors.forename: Z
authors.initials: Z
authors.lastname: Galdzicki
authors.forename: R
authors.initials: R
authors.lastname: Siarey
authors.forename: R
authors.initials: R
authors.lastname: Pearce
authors.forename: J
authors.initials: J
authors.lastname: Stoll
authors.forename: S I
authors.initials: SI
authors.lastname: Rapoport
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology