Cognitive enhancement by pharmacological and behavioral interventions: the murine Down syndrome model

Topic: Brain proteins, microglia and lab models

The cognitive deficits in Down syndrome (DS) are attributed to an excessive hippocampal inhibition, which obstructs neuronal plasticity and normal learning and memory, a view which is largely based on studies of Ts65Dn mice, the best characterized mouse model of DS. The cognitive behavioral deficits of Ts65Dn mice can be rescued by reducing GABAergic inhibition, most selectively by partial inverse agonists acting on α(5) GABA-A receptors, of which one compound has recently entered clinical trials in DS. Most remarkably, the improved cognitive performance of Ts65Dn can persist for weeks and months after cessation of drug treatment, as demonstrated for the non-specific GABA antagonist pentylenetetrazole. The Alzheimer drugs, memantine and donepezil largely fail to show any benefit. Finally, repeated non-invasive sensory stimulation such as over-training or enriching the environment, are able to enhance the learning performance which underlines the reversibility of an obstructed neuronal plasticity in Ts65Dn mice.

@article{mohler2012-22898099,
  author  = {Möhler, H.},
  title   = {{Cognitive enhancement by pharmacological and behavioral interventions: the murine Down syndrome model}},
  journal = {Biochemical pharmacology},
  year    = {2012},
  doi     = {10.1016/j.bcp.2012.06.028},
  pmid    = {22898099},
  url     = {https://doi.org/10.1016/j.bcp.2012.06.028}
}

Key findings

• Most remarkably, the improved cognitive performance of Ts65Dn can persist for weeks and months after cessation of drug treatment, as demonstrated for the non-specific GABA antagonist pentylenetetrazole.

Why it matters

In the Ts65Dn mouse model of Down syndrome, reducing GABAergic inhibition improved cognitive performance, and the Alzheimer drugs memantine and donepezil largely failed to show any benefit. These are mouse findings, though one compound acting on α5 GABA-A receptors has entered clinical trials in Down syndrome.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.bcp.2012.06.028
• PubMed: 22898099
• Original source →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Cognitive deficits and associated neurological complications in individuals with Down's syndrome The Lancet. Neurology · 2010-06-01 · usefulness score 53/100 · Getting a diagnosis

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• Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome Translational neurodegeneration · 2018-11-06 · usefulness score 47/100
• Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts65Dn mouse model of Down syndrome Behavioral neuroscience · 2010-06-01 · usefulness score 36/100
• Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions Antioxidants (Basel, Switzerland) · 2026-04-21 · usefulness score 39/100
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Also tagged “down”

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• Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down Syndrome: quantitative comparison with Alzheimer dementia Annals of neurology · 1980-05-01 · usefulness score 43/100 · Down syndrome and Alzheimer's
• Tubulin immunopositive structures resembling intracellular neurofibrillary tangles Neurobiology of aging · 1998-01-01 · usefulness score 32/100 · Down syndrome and Alzheimer's
• A fibril-specific, conformation-dependent antibody recognizes a subset of Abeta plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain Acta neuropathologica · 2009-04-10 · usefulness score 42/100 · Down syndrome and Alzheimer's

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More on Down syndrome and Alzheimer's

• A review that covers this ground Psychiatric and behavioral disorders in persons with Down syndrome Mental retardation and developmental disabilities research reviews · 2007-01-01 · usefulness score 36/100
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