Abstract
Down syndrome (DS) is caused by the overexpression of genes on triplicated regions of human chromosome 21 (Hsa21). While the resulting physiological and behavioral phenotypes vary in their penetrance and severity, all individuals with DS have variable but significant levels of cognitive disability. At the core of cognitive processes is the phenomenon of synaptic plasticity, a functional change in the strength at points of communication between neurons. A wide variety of evidence from studies on DS individuals and mouse models of DS indicates that synaptic plasticity is adversely affected in human trisomy 21 and mouse segmental trisomy 16, respectively, an outcome that almost certainly extensively contributes to the cognitive impairments associated with DS. In this review, we will highlight some of the neurophysiological changes that we believe reduce the ability of trisomic neurons to undergo neuroplasticity-related adaptations. We will focus primarily on hippocampal networks which appear to be particularly impacted in DS and where consequently the majority of cellular and neuronal network research has been performed using DS animal models, in particular the Ts65Dn mouse. Finally, we will postulate on how altered plasticity may contribute to the DS cognitive disability.
Highlights
Down syndrome (DS) results from the triplication of genes on human chromosome 21 (Hsa21) and is associated with a range of phenotypes including craniofacial changes [1, 2], cardiac defects [3], susceptibility to leukemia but with reduced occurrence of solid cancers [4, 5], and intellectual disability [6, 7]
The link between synaptic plasticity and cognitive processes such as learning and memory is frequently studied within the hippocampus, a structure involved in diverse cognitive processes such as those related to acquisition, coding, storing, and recalling information in physical or perceived spatial environments [14,15,16]
In Ts65Dn mice, we found that Protein kinase A (PKA) activity is reduced in the hippocampus [93], which should adversely affect longterm potentiation (LTP) by reducing protein expression required for the late phase
Summary
Down syndrome (DS) results from the triplication of genes on human chromosome 21 (Hsa21) and is associated with a range of phenotypes including craniofacial changes [1, 2], cardiac defects [3], susceptibility to leukemia but with reduced occurrence of solid cancers [4, 5], and intellectual disability [6, 7]. The link between synaptic plasticity and cognitive processes such as learning and memory is frequently studied within the hippocampus, a structure involved in diverse cognitive processes such as those related to acquisition, coding, storing, and recalling information in physical or perceived spatial environments [14,15,16]. Multiple lines of Neural Plasticity evidence indicate that long-lasting up- or downregulation of functional synaptic strengths, referred to as longterm potentiation (LTP) and long-term depression (LTD), respectively, are fundamental synaptic mechanisms underlying hippocampal contributions to these processes. We will provide an overview of the morphological and behavioral evidence for altered synaptic plasticity in DS with a focus on the hippocampus and discuss the insights provided by mouse models of this neurodevelopmental disorder into the potential molecular mechanisms contributing to these deficits
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