The notion that DS symptoms represent an irreversible developmental defect has been challenged recently by demonstrations that cognition in Ts65Dn mice can be improved pharmacologically using either GABAA
, memantine (an NMDA receptor antagonist) 
, or the noradrenergic agonist prodrug, L-DOPS 
. Together these observations suggest that cognitive improvement in Ts65Dn mice occurs by enhancing or otherwise regulating excitatory synaptic transmission. This is consistent with observations suggesting that GABAergic over-inhibition of excitatory synaptic activity causes loss of synaptic plasticity in Ts65Dn mice 
. Here we provide evidence that cognitive deficits in DS can be corrected by controlling Aβ production, itself a regulator of glutamatergic transmission. Specifically, we propose that the cognitive improvement we observed in Ts65Dn mice treated with the γ-secretase inhibitor, DAPT, resulted from lowered Aβ levels 
Our results contribute to a growing body of evidence that supports the hypothesis that cognitive function undergoes rapid change in response to fluctuations in soluble Aβ levels in cognitively impaired animals. Administration of DAPT to the Alzheimer's mouse model, Tg2576 corrects cognitive deficits characteristic of this strain after exposing the mice to the drug for as little as 3 hours prior to testing 
. Tg2576 mice express human APP containing the familial Alzheimer's disease (FAD) Swedish mutation, which results in elevated levels of Aβ peptides 
. Tg2576 mice begin to develop amyloid plaques at about 12+ months. However, soluble Aβ levels are elevated by five months and the mice are cognitively impaired at this time. The rapid correction of the cognitive deficit in these mice, ages 5 to 16 months, by DAPT administered only 3 hours prior to testing coincides with the amount of time required to reduce levels of soluble Aβ by about one half 
Other studies have shown that soluble Aβ rapidly inhibits hippocampal long-term potentiation (LTP) in vivo 
and depresses excitatory synaptic transmission in hippocampal slice neurons 
. A mechanism that would account for these effects of Aβ is suggested by studies in which soluble Aβ has been shown to induce rapid internalization of NMDA- 
and AMPA-type glutamate receptors 
. These cellular events suggest a mechanism that could explain reduced cognitive function in the context of Aβ overexpression as well as the rapid recovery of cognitively impaired animals treated with Aβ-lowering drugs.
In human DS, children exhibit intellectual disability prior to the development of a neurodegenerative phenotype or the development of amyloid plaques 
. This does not rule out developmental abnormalities as contributors to intellectual disability. However, given the rapid amelioration of cognitive deficits in Ts65Dn mice by DAPT, we suggest that intellectual disability in young DS patients might also be treatable by Aβ-lowering drugs.