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


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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    • "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.
    Neurobiology of Disease 03/2015; 77. DOI:10.1016/j.nbd.2015.02.022 · 5.08 Impact Factor
    • "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
    Reviews in the neurosciences 03/2015; 26(3):253-268. DOI:10.1515/revneuro-2014-0075 · 3.33 Impact Factor
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    • "More excitingly, these observations demonstrate the potential of pharmacological therapies for neurodevelopmental disorders. The list of ARDs that have been reversed in adult symptomatic mice continues to grow, and also includes RTT [231], DS [232] [233], and AS [92]. Together, these findings demonstrate the remarkable plastic nature of the brain and imply that if the causal denominator of ARDs could be found and therapeutically targeted, we may be able to allow the ARD brain to rewire itself and relieve clinical symptoms once believed to be irreversible. "
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    ABSTRACT: The activity-dependent structural and functional plasticity of dendritic spines has led to the long-standing belief that these neuronal compartments are the subcellular sites of learning and memory. Of relevance to human health, central neurons in several neuropsychiatric illnesses, including autism related disorders, have atypical numbers and morphologies of dendritic spines. These so-called dendritic spine dysgeneses found in individuals with autism related disorders are consistently replicated in experimental mouse models. Dendritic spine dysgenesis reflects the underlying synaptopathology that drives clinically relevant behavioral deficits in experimental mouse models, providing a platform for testing new therapeutic approaches. By examining molecular signaling pathways, synaptic deficits, and spine dysgenesis in experimental mouse models of autism related disorders we find strong evidence for mTOR to be a critical point of convergence and promising therapeutic target. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Neuroscience Letters 01/2015; 601. DOI:10.1016/j.neulet.2015.01.011 · 2.03 Impact Factor
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