Memantine Normalizes Several Phenotypic Features in the Ts65Dn Mouse Model of Down Syndrome

Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2010; 21(1):277-90. DOI: 10.3233/JAD-2010-100240
Source: PubMed


Ts65Dn (TS) mice exhibit several phenotypic characteristics of human Down syndrome, including an increased brain expression of amyloid-beta protein precursor (AbetaPP) and cognitive disturbances. Aberrant N-methyl-D-aspartate (NMDA) receptor signaling has been suspected in TS mice, due to an impaired generation of hippocampal long-term potentiation (LTP). Memantine, an uncompetitive NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease, is known to normalize LTP and improve cognition in transgenic mice with high brain levels of AbetaPP and amyloid-beta protein. It has recently been demonstrated that acute injections of memantine rescue performance deficits of TS mice on a fear conditioning test. Here we show that oral treatment of aged TS mice with a clinically relevant dose of memantine (30 mg/kg/day for 9 weeks) improved spatial learning in the water maze task and slightly reduced brain AbetaPP levels. We also found that TS mice exhibited a significantly reduced granule cell count and vesicular glutamate transporter-1 (VGLUT1) labeling compared to disomic control mice. After memantine treatment, the levels of hippocampal VGLUT1 were significantly increased, reaching the levels observed in vehicle treated-control animals. Memantine did not significantly affect granule cell density. These data indicate that memantine may normalize several phenotypic abnormalities in TS mice, many of which--such as impaired cognition--are also associated with Down syndrome and Alzheimer's disease.

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    • "In general, expression of proteins involved in glutamate transport is decreased when DYRK1A is increased and increased when DYRK1A is decreased. Ts65Dn mice exhibit significantly reduced vesicular glutamate transporter-1 (VGLUT1) labeling compared to euploid control mice (Rueda et al., 2010). In parallel with these results, we observed an effect of Dyrk1a dosage on NR1, NR2A, GLUR1, GLUR2, and the activated form of CAMKII, components of the synaptic machinery that are generally decreased in mBACtgDyrk1a and increased in Dyrk1a(+/−). "
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    ABSTRACT: Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/−) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/−) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance towards inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations.
    Neurobiology of Disease 09/2014; 69. DOI:10.1016/j.nbd.2014.04.016 · 5.08 Impact Factor
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    • "Some of these are of particular relevance to the possibility of premature aging in these mice. For example, memantine, a drug used in humans to treat AD, appears to improve learning and memory in Ts65Dn [47] [48] [49]. Treatment of young (4 month old) Ts65Dn mice with a gamma secretase inhibitor has been reported to rescue learning and memory, potentially implicating the amyloid precursor protein (APP) or its metabolites in learning and memory deficits, even at an early age [50]. "
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    ABSTRACT: Down syndrome is a complex condition caused by trisomy of human chromosome 21. The biology of aging may be different in individuals with Down syndrome; this is not well understood in any organism. Because of its complexity, many aspects of Down syndrome must be studied either in humans or in animal models. Studies in humans are essential but are limited for ethical and practical reasons. Fortunately, genetically altered mice can serve as extremely useful models of Down syndrome, and progress in their production and analysis has been remarkable. Here, we describe various mouse models that have been used to study Down syndrome. We focus on segmental trisomies of mouse chromosome regions syntenic to human chromosome 21, mice in which individual genes have been introduced, or mice in which genes have been silenced by targeted mutagenesis. We selected a limited number of genes for which considerable evidence links them to aspects of Down syndrome, and about which much is known regarding their function. We focused on genes important for brain and cognitive function, and for the altered cancer spectrum seen in individuals with Down syndrome. We conclude with observations on the usefulness of mouse models and speculation on future directions.
    Current Gerontology and Geriatrics Research 02/2012; 2012:717315. DOI:10.1155/2012/717315
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    • "These and other observations suggest that restricting activation of the NMDA receptors may have beneficial effects on homeostasis of intracellular calcium and, possibly, cognition in DS model mice. Indeed, several recent studies described significant improvement of Ts65Dn mice in hippocampus-mediated memory tests following acute and/or chronic treatment with memantine, an uncompetitive partial antagonist of the NMDA receptors (Costa et al., 2008; Lockrow et al., 2011; Rueda et al., 2010). Memantine has been approved in the USA and Europe for moderate to severe dementia and was recently proposed for a clinical trial in people with DS (Costa, 2011). "
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    ABSTRACT: This review describes recent discoveries in neurobiology of Down syndrome (DS) achieved with use of mouse genetic models and provides an overview of experimental approaches aimed at development of pharmacological restoration of cognitive function in people with this developmental disorder. Changes in structure and function of synaptic connections within the hippocampal formation of DS model mice, as well as alterations in innervations of the hippocampus by noradrenergic and cholinergic neuromodulatory systems, provided important clues for potential pharmacological treatments of cognitive disabilities in DS. Possible molecular and cellular mechanisms underlying this genetic disorder have been addressed. We discuss novel mechanisms engaging misprocessing of amyloid precursor protein (App) and other proteins, through their affect on axonal transport and endosomal dysfunction, to "Alzheimer-type" neurodegenerative processes that affect cognition later in life. In conclusion, a number of therapeutic strategies have been defined that may restore cognitive function in mouse models of DS. In the juvenile and young animals, these strategists focus on restoration of synaptic plasticity, rate of adult neurogenesis, and functions of the neuromodulatory subcortical systems. Later in life, the major focus is on recuperation of misprocessed App and related proteins. It is hoped that the identification of an increasing number of potential targets for pharmacotherapy of cognitive deficits in DS will add to the momentum for creating and completing clinical trials.
    Progress in brain research 01/2012; 197:199-221. DOI:10.1016/B978-0-444-54299-1.00010-8 · 2.83 Impact Factor
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