Abstract
Ts65Dn mice, a model for Down syndrome, have excessive inhibition in the dentate gyrus, a condition that could compromise synaptic plasticity and mnemonic processing. We show that chronic systemic treatment of these mice with GABAA antagonists at non-epileptic doses causes a persistent post-drug recovery of cognition and long-term potentiation. These results suggest that over-inhibition contributes to intellectual disabilities associated with Down syndrome and that GABAA antagonists may be useful therapeutic agents for this disorder.
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Acknowledgements
We thank the Down Syndrome Research and Treatment Foundation (DSRTF), the Hillblom Foundation, the US National Science Foundation (NSF), the US National Institute of Health (NIH), Jax West Laboratories, the Stanford Down Syndrome Center and W.C. Mobley for their support.
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F.F. designed and executed all behavioral experiments with the assistance of E.Z. and J.N. W.M. performed all of the electrophysiology experiments. M.B. provided technical expertise in breeding and genotyping. F.F., C.C.G., W.M. and R.C.M. wrote and edited the manuscript.
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Supplementary information
Supplementary Fig. 1
Ts65Dn mice exhibit declarative memory problems, but intact procedural learning. (PDF 101 kb)
Supplementary Fig. 2
Chronic but not acute administration of picrotoxin (PTX) normalizes Ts65Dn performance in the novel object recognition task. (PDF 94 kb)
Supplementary Table 1
Tabulated discrimination indices (DI's) in the novel object recognition task. (PDF 148 kb)
Supplementary Table 2
Picrotoxin (PTX), bilobalide (BB) and pentylenetetrazole (PTZ) do not affect exploration times in the novel object recognition task. (PDF 148 kb)
Supplementary Table 3
Tabulated alternation percentages (%) in the spontaneous alternation task. (PDF 154 kb)
Supplementary Table 4
Pentylenetetrazole (PTZ) does not affect arm entries in the spontaneous alternation task. (PDF 147 kb)
Supplementary Discussion
Potential utility of non-competitive GABAA receptor antagonists for the treatment of cognitive impairment in Down syndrome. (PDF 97 kb)
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Fernandez, F., Morishita, W., Zuniga, E. et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci 10, 411–413 (2007). https://doi.org/10.1038/nn1860
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DOI: https://doi.org/10.1038/nn1860