Article

Garner CC Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome

Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, Palo Alto, California 94304-5485, USA.
Nature Neuroscience (Impact Factor: 16.1). 05/2007; 10(4):411-3. DOI: 10.1038/nn1860
Source: PubMed

ABSTRACT

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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    • "Finally, we observed that LTP in DG MML was deficient in the TTS mice. Similar changes in LTP were previously demonstrated in Ts65Dn [26,30,38] and all the models in which LTP was tested in DG [45,65,115]. Importantly, the conservation of decreased LTP in the DG was accompanied by evidence of normalization using picrotoxin to block GABAA receptors. "
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    ABSTRACT: Down syndrome (DS), trisomy for chromosome 21, is the most common genetic cause of intellectual disability. The genomic regions on human chromosome 21 (HSA21) are syntenically conserved with regions on mouse chromosomes 10, 16, and 17 (Mmu10, Mmu16, and Mmu17). Recently, we created a genetic model of DS which carries engineered duplications of all three mouse syntenic regions homologous to HSA21. This 'triple trisomic' or TTS model thus represents the most complete and accurate murine model currently available for experimental studies of genotype-phenotype relationships in DS. Here we extended our initial studies of TTS mice. Locomotor activity, stereotypic and repetitive behavior, anxiety, working memory, long-term memory, and synaptic plasticity in the dentate gyrus were examined in the TTS and wild-type (WT) control mice. Changes in locomotor activity were most remarkable for a significant increase in ambulatory time and a reduction in average velocity of TTS mice. No changes were detected in repetitive and stereotypic behavior and in measures of anxiety. Working memory showed no changes when tested in Y-maze, but deficiency in a more challenging T-maze test was detected. Furthermore, long-term object recognition memory was significantly reduced in the TTS mice. These changes were accompanied by deficient long-term potentiation in the dentate gyrus, which was restored to the WT levels following blockade of GABAA receptors with picrotoxin (100 μM). TTS mice thus demonstrated a number of phenotypes characteristic of DS and may serve as a new standard by which to evaluate and direct findings in other less complete models of DS.
    Full-text · Article · Aug 2015 · PLoS ONE
    • "Synaptic abnormalities include reduced dendritic spine density, increased spine size, increased active zone length in specific synapse subtypes, and decreased levels of pre-and postsynaptic markers (Belichenko et al., 2004; Chakrabarti et al., 2007; Kurt et al., 2004; Salehi et al., 2006). Increased GABA A and GABA B -mediated inhibitory neurotransmission is responsible for deficient long term potentiation in hippocampus (Belichenko et al., 2004; Fernandez et al., 2007; Kleschevnikov et al., 2012b, 2004; Siarey et al., 1997). DS and AD brains exhibit increased size and number of Rab5- immunopositive early endosomes; in DS this phenotype is evident during the first year of life (Cataldo et al., 1997, 2008, 2000; Ginsberg et al., 2010). "
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    ABSTRACT: Down Syndrome (DS), trisomy 21, is characterized by synaptic abnormalities and cognitive deficits throughout the lifespan and with development of Alzheimer's disease (AD) neuropathology and progressive cognitive decline in adults. Synaptic abnormalities are also present in the Ts65Dn mouse model of DS, but which synapses are affected and the mechanisms underlying synaptic dysfunction are unknown. Here we show marked increases in the levels and activation status of TrkB and associated signaling proteins in cortical synapses in Ts65Dn mice. Proteomic analysis at the single synapse level of resolution using array tomography (AT) uncovered increased colocalization of activated TrkB with signaling endosome related proteins, and demonstrated increased TrkB signaling. The extent of increases in TrkB signaling differed in each of the cortical layers examined and with respect to the type of synapse, with the most marked increases seen in inhibitory synapses. These findings are evidence of markedly abnormal TrkB-mediated signaling in synapses. They raise the possibility that dysregulated TrkB signaling contributes to synaptic dysfunction and cognitive deficits in DS. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Mar 2015 · Neurobiology of Disease
    • "A great majority of studies have shown that uncontrolled levels of inhibition in the medial temporal lobe of Ts65Dn mice caused a failure of long-term synaptic plasticity in their hippocampus, resulting in cognitive impairment ( Kleschevnikov et al., 2004 ; Fernandez et al., 2007 ). "
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    ABSTRACT: Deciphering the cellular and molecular mechanisms of memory has been an important topic encompassing the learning and memory domain besides the neurodegenerative disorders. Synapses accumulate cognitive information from life-lasting alterations of their molecular and structural composition. Current memory storage models identify posttranslational modification imperative for short-term information storage and mRNA translation for long-term information storage. However, the precise account of these modifications has not been summarized at the individual synapse level. Therefore, herein we describe the spatiotemporal reorganization of synaptic plasticity at the dendritic spine level to elucidate the mechanism through which synaptic substructures are remodeled; though at the molecular level, such mechanisms are still quite unclear. It has thus been concluded that the existing mechanisms do not entirely elaborate memory storage processes. Further efforts are therefore encouraged to delineate the mechanism of neuronal connectivity at the chemical level as well, including inter- or intramolecular bonding patterns at the synaptic level, which may be a permissive and vital step of memory storage
    No preview · Article · Mar 2015 · Reviews in the neurosciences
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