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Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome


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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Figure 1: PTX and BB rescue Ts65Dn performance in the novel object recognition task.
Figure 2: PTZ elicits long-lasting cognitive improvement in Ts65Dn mice.
Figure 3: PTZ rescues LTP at medial perforant path–granule cell synapses in Ts65Dn mice.


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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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Authors and Affiliations



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.

Corresponding author

Correspondence to Craig C Garner.

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The authors declare no competing financial interests.

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)

Supplementary Methods (PDF 104 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).

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