Garner CC Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome
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.
Full-textDOI: · Available from: Martina Blank, Sep 28, 2015
- SourceAvailable from: Lucas Pozzo-Miller
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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 , DS  , and AS . 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. "
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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- "Values are mean values±S.E.M. n≥10, ⁎ Pb.05, ⁎⁎ Pb.01. door was removed, and the rats were allowed to freely explore the rest of the maze for an 8-min trial  . Numbers of visits to each goal arm and spontaneous alternation performance were recorded by the observer. "
ABSTRACT: Prenatal stress is known to induce emotional and cognitive dysfunction in the offspring of both humans and experimental animals. Hydroxytyrosol (HT), a major polyphenol in olive oil with reported ability modulating oxidative stress and mitochondrial function, was performed to investigate its preventive effect on prenatal stress-induced behavioral and molecular alterations in offspring. Rats were exposed to restraint stress on days 14–20 of pregnancy. HT was given at doses of 10 and 50 mg/kg/day. The spontaneous alternation performance and Morris water maze confirmed the impaired learning capacity and memory performance induced by prenatal stress in both male and female offspring, and these effects were markedly restored in the HT supplement groups. Through tissue analysis of the hippocampi of male offspring, we found that the stress-induced downregulation of neural proteins, including BDNF, GAP43, synaptophysin, NMDAR1, NMDANR2A and NMDANR2B, was prevented by HT. Prenatal stress-induced low expression of glucocorticoid receptor was also increased by HT, although basal fetal serum corticosterone levels were not different among the four groups. Oxidative stress and mitochondrial dysfunction in prenatally stressed rats were confirmed with changes in protein oxidation, SOD activity, the expression of mitochondrial complexes and mitochondrial DNA copy number. Meanwhile, HT significantly increased transcription factors FOXO1 and FOXO3, as well as phase II enzyme-related proteins, including Nrf2 and HO-1, which may contribute to the decreased oxidative stress and increased mitochondrial function shown with HT supplementation. Taken together, these findings suggest that HT is an efficient maternal nutrient protecting neurogenesis and cognitive function in prenatally stressed offspring.The Journal of Nutritional Biochemistry 11/2014; DOI:10.1016/j.jnutbio.2014.10.006 · 3.79 Impact Factor
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- "Numerous studies have demonstrated that the cognitive impairment exhibited by the TS mouse model of DS is due to an imbalance between excitatory and inhibitory neurotransmission, leading to excessive levels of neuronal inhibition (see , ). In particular, the marked reduction in LTP in the CA1 and DG areas of the hippocampus has been associated with enhanced GABA-mediated inhibition –, as the impairments in synaptic plasticity and cognitive disturbances could be rescued in the TS mouse by administering various antagonists or negative allosteric modulators of the GABAA receptor , , , , . Consistent with the increased levels of GABAergic synaptic proteins in the cortex and hippocampus of TS mice , , , in this study, we found enhanced expression of GAD65/67, which is a marker of GABAergic synapses, and reduced expression of VGLUT, which is a marker of glutamatergic synapses. "
ABSTRACT: Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/-) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities.PLoS ONE 09/2014; 9(9):e106572. DOI:10.1371/journal.pone.0106572 · 3.23 Impact Factor