Understanding mental retardation in Down's syndrome using trisomy 16 mouse models

Abstract

Mental retardation in Down's syndrome, human trisomy 21, is characterized by developmental delays, language and memory deficits and other cognitive abnormalities. Neurophysiological and functional information is needed to understand the mechanisms of mental retardation in Down's syndrome. The trisomy mouse models provide windows into the molecular and developmental effects associated with abnormal chromosome numbers. The distal segment of mouse chromosome 16 is homologous to nearly the entire long arm of human chromosome 21. Therefore, mice with full or segmental trisomy 16 (Ts65Dn) are considered reliable animal models of Down's syndrome. Ts65Dn mice demonstrate impaired learning in spatial tests and abnormalities in hippocampal synaptic plasticity. We hypothesize that the physiological impairments in the Ts65Dn mouse hippocampus can model the suboptimal brain function occuring at various levels of Down's syndrome brain hierarchy, starting at a single neuron, and then affecting simple and complex neuronal networks. Once these elements create the gross brain structure, their dysfunctional activity cannot be overcome by extensive plasticity and redundancy, and therefore, at the end of the maturation period the mind inside this brain remains deficient and delayed in its capabilities. The complicated interactions that govern this aberrant developmental process cannot be rescued through existing compensatory mechanisms. In summary, overexpression of genes from chromosome 21 shifts biological homeostasis in the Down's syndrome brain to a new less functional state.

On dendrites in Down syndrome and DS murine models: a spiny way to learn

“…The abnormalities in Ts16 hippocampal neurons are opposite in direction to abnormalities in Ts16 DRG neurons, indicating that there is not a common membrane electrical abnormality in all Ts16 neuronal types. The cell-type differences may reflect, however, a common defect in signal transduction possibly involving channel phosphorylation (see Galdzicki and Siarey, 2003). Selective failure of BDNFdependent survival in cultured hippocampal neurons from the Ts16 mouse has been described.…”

“…In Ts65Dn mice, abnormalities in the duration of the action potential and its rates of depolarisation and repolarisation, altered kinetics of active Na + , Ca 2+ and K + currents, and altered membrane densities of Na + and Ca 2+ channels have been observed (see Galdzicki and Siarey, 2003 for review). Furthermore, electrophysiological studies of the CA1 region of the hippocampus from the adult Ts65Dn mouse show synaptic plasticity changes that lead to abnormalities in LTP and LTD, models of learning and memory (Siarey et al, 1999;Galdzicki and Siarey, 2003).…”

“…The varied approaches used to study the consequences of increased gene dosage in DS and to investigate phenotype/ genotype relationships of HSA21 genes in mice (see Cairns, 2001;Galdzicki and Siarey, 2003 for review) are: (1) transgenic animals overexpressing single or combinations of genes, (2) transgenic mice with large foreign DNA pieces introduced on yeast artificial chromosomes (YACs) or bacterial artificial chromosomes into mice (Smith et al, 1995(Smith et al, , 1997, (3) mouse models that carry all or part of MMU16, which has regions of conserved homology with HSA21 and (4) chimaeric mice that carry a fragment of human chromosome 21 (Tomizuca et al, 1997).…”

Defects in Embryonic Neurogenesis and Initial Synapse Formation in the Forebrain of the Ts65Dn Mouse Model of Down Syndrome

“…1) (Kola and Hertzog, 1998;Dierssen et al, 2001;Galdzicki and Siarey, 2003;Seregaza et al, 2006). We previously discovered delays in neocortical development in the trisomy 16 (Ts16) mouse (Haydar et al, 1996(Haydar et al, , 2000Cheng et al, 2004), but it is now accepted that the presence of non-HSA21 homologous genes in Ts16 prevents valid comparisons to DS brain development.…”

Novel Animal Models of Pediatric Epilepsy

“…The Down Syndrome Model -Ts65Dn Mice A mouse model of Down syndrome (Ts65Dn) has been developed to study many aspects of this genetic disorder [57]. Ts65Dn mice exhibit spontaneous spike-wave discharges in EEG recordings without any seizures at baseline [58].…”