Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome
Open accessAbstract
Although many genetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 (trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABA A receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.
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Mouse models of DS have elucidated specific defects in neurogenesis, neuronal differentiation, and impaired synaptic plasticity and learning.
“Mouse models have provided additional insights into the developmental progression of DS, elucidating specific defects in neurogenesis, neuronal differentiation, and impaired synaptic plasticity and learning (Chakrabarti et al., 2007, 2010; Hyde et al., 2001; Kleschevnikov et al., 2004; Siarey et al., 1997, 1999; Tyler and Haydar, 2013; Wang et al., 2013).”
From Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination (2016) · cites this paper as Kleschevnikov et al., 2004
The Results section ('Failed induction of LTP'; page unavailable) reports impaired hippocampal long-term potentiation in Ts65Dn mice, and the Discussion describes learning and memory deficits in these mice. The paper does not establish the cited sentence’s claims about defects in neurogenesis or neuronal differentiation, or their developmental progression. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFindings from mouse models of Down syndrome, particularly the Ts65Dn model, show reduced long-term potentiation and increased long-term depression, reflecting the relative strengthening and weakening, respectively, of individual synapses.
“This suggestion is largely driven by findings from mouse models of DS, particularly the Ts65Dn model, in which patch clamp electrophysiology analyses reveal reduced long-term potentiation (LTP) and increased long-term depression (LTD), reflecting the relative strengthening and weakening, respectively, of individual synapses123–126.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [126]
The section ‘Failed induction of LTP and inadequate synaptic activation of NMDA receptors in Ts65Dn mice’ reports that LTP was not induced in Ts65Dn dentate-gyrus slices. The paper’s LTP measurements used field-potential recordings, while its whole-cell recordings assessed inhibitory currents. Its finding of increased paired-pulse depression reflects stronger feedback inhibition, not increased long-term depression (LTD); no page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn Ts65Dn hippocampus, long-term potentiation (LTP) induction fails due to excessive GABA-mediated inhibition.
“A seminal study in the field found failure of induction of long-term potentiation (LTP) in the Ts65Dn hippocampus due to excessive GABA-mediated inhibition and a wide array of following studies have confirmed this finding (Siarey et al., 1997, 1999; Kleschevnikov et al., 2004; Costa and Grybko, 2005; Fernandez et al., 2007).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Kleschevnikov et al., 2004
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“A seminal study in the field found failure of induction of long-term potentiation (LTP) in the Ts65Dn hippocampus due to excessive GABA-mediated inhibition and a wide array of following studies have confirmed this finding (Siarey et al., 1997, 1999; Kleschevnikov et al., 2004; Costa and Grybko, 2005; Fernandez et al.,…”
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“…findings from mouse models of DS, particularly the Ts65Dn model , in which patch clamp electrophysiology analyses reveal reduced long-term potentiation (LTP) and increased long-term depression (LTD), reflecting the relative strengthening and weakening, respectively, of individual synapses 123–126 .”
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- Authors
- Kleschevnikov, A. M., Belichenko, P. V., Villar, A. J., Epstein, C. J., Malenka, R. C., & Mobley, W. C.
- Affiliations
- Stanford Medicine (US)
- Institute for Neuroscience (CH)
- University of California, San Francisco (US)
- Corresponding author
- Kleschevnikov, Alexander M.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-09-15
- Volume
- 24
- Issue
- 37
- Pages
- 8153-8160
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729789
- OpenAlex
- W2154768876
- Cited by
- 459
- References
- 5
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 13 · 2023: 13 · 2022: 19 · 2021: 20 · 2020: 17 · 2019: 25 · 2018: 16 · 2017: 23 · 2016: 26 · 2015: 23 · 2014: 31 · 2013: 25 · 2012: 32
- FWCI
- 20.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Larry L. Hillblom Foundation
- Down Syndrome Research and Treatment Foundation
- National Institutes of Health (5r01hd031498-05)
- National Institute on Aging (R01AG016999, AG 16999)
- National Institute of Neurological Disorders and Stroke (NS 38869, R01NS038869)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-31498)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- Down syndrome, Ts65Dn mouse model, hippocampus, long-term potentiation, NMDA receptor, synaptic inhibition, dentate gyrus, picrotoxin, GABAA receptor, learning and memory impairment, developmental disorders
- MeSH terms
- Animals, Cognition Disorders, Crosses, Genetic, Disease Models, Animal, Down Syndrome, Evoked Potentials, Female, Glycine, Hippocampus, Magnesium, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Mutant Strains, Picrotoxin, Quinoxalines, Species Specificity, Trisomy, 2-Amino-5-phosphonovalerate, Receptors, N-Methyl-D-Aspartate, Presynaptic Terminals, Long-Term Potentiation, Patch-Clamp Techniques, Gene Dosage, Dentate Gyrus, Mice, GABA-A Receptor Antagonists
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