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Cited by 124Down syndrome and intellectual disability researchNeuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental Disorders

Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome

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Kleschevnikov, Alexander M., Belichenko, Pavel V., Gall, Jessica, George, Lizzy, Nosheny, Rachel, Maloney, Michael T., Salehi, Ahmad, Mobley, William C.·2012·Neurobiology of Disease
DOI 10.1016/j.nbd.2011.10.009PMC PMC3259223
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Abstract

Cognitive impairment in Down syndrome (DS) involves the hippocampus. In the Ts65Dn mouse model of DS, deficits in hippocampus-dependent learning and synaptic plasticity were linked to enhanced inhibition. However, the mechanistic basis of changes in inhibitory efficiency remains largely unexplored, and efficiency of the GABAergic synaptic neurotransmission has not yet been investigated in direct electrophysiological experiments. To investigate this important feature of neurobiology of DS, we examined synaptic and molecular properties of the GABAergic system in the dentate gyrus (DG) of adult Ts65Dn mice. Both GABAA and GABAB receptor-mediated components of evoked inhibitory postsynaptic currents (IPSCs) were significantly increased in Ts65Dn vs. control (2N) DG granule cells. These changes were unaccompanied by alterations in hippocampal levels of GABAA (α1, α2, α3, α5 and γ2) or GABAB (Gbr1a and Gbr1b) receptor subunits. Immunoreactivity for GAD65, a marker for GABAergic terminals, was also unchanged. In contrast, there was a marked change in functional parameters of GABAergic synapses. Paired stimulations showed reduced paired-pulse ratios of both GABAA and GABAB receptor-mediated IPSC components (IPSC2/IPSC1), suggesting an increase in presynaptic release of GABA. Consistent with increased gene dose, the level of the Kir3.2 subunit of potassium channels, effectors for postsynaptic GABAB receptors, was increased. This change was associated with enhanced postsynaptic GABAB/Kir3.2 signaling following application of the GABAB receptor agonist baclofen. Thus, both GABAA and GABAB receptor-mediated synaptic efficiency is increased in the Ts65Dn DG, thus likely contributing to deficient synaptic plasticity and poor learning in DS.

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  • Findings 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 [125]

    The Introduction and Discussion link abnormal synaptic plasticity in Ts65Dn mice to enhanced inhibition, and the References list a study of suppressed hippocampal LTP. But this paper’s electrophysiological results concern GABAergic transmission and paired-pulse responses; our copy does not report increased LTD or show that its recordings measured LTP and LTD. (LLM, conf=0.81)

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Authors
Kleschevnikov, A. M., Belichenko, P. V., Gall, J., George, L., Nosheny, R., Maloney, M. T., Salehi, A., & Mobley, W. C.
Affiliations
  • University of California San Diego (US)
  • Stanford Medicine (US)
  • Stanford University (US)
  • VA Palo Alto Health Care System (US)
Corresponding author
Kleschevnikov, Alexander M.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2012-02
Volume
45
Issue
2
Pages
683-691
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2011.10.009
PMC
PMC3259223
OpenAlex
W2066636162
Cited by
124
References
6
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 4 · 2017: 11 · 2016: 9 · 2015: 10 · 2014: 13 · 2013: 10 · 2012: 11
FWCI
11.01
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Neurological Disorders and Stroke (R01NS066072)
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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Down syndrome, Ts65Dn mouse model, GABAA receptor, GABAB receptors, GABAergic neurotransmission, inhibitory postsynaptic currents, dentate gyrus granule cells, hippocampus, paired-pulse ratio, presynaptic GABA release, baclofen, synaptic plasticity, learning deficits, GAD65
MeSH terms
Animals, Disease Models, Animal, Down Syndrome, Immunohistochemistry, Synaptic Transmission, Receptors, GABA-A, Blotting, Western, Receptors, GABA-B, Patch-Clamp Techniques, Dentate Gyrus, Mice, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Inhibitory Postsynaptic Potentials

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