Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine

Scott-McKean, Jonah J.; Costa, Alberto C. S.

doi:10.1101/lm.024182.111

Cited by 41 publications

(39 citation statements)

References 38 publications

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“…This latter effect can be reversed with the uncompetitive NMDA receptor antagonist memantine [78] and also improves the cognitive performance of Ts65Dn mice [79–81]. These results draw a clear link between altered synaptic plasticity in the hippocampus and cognitive performance in the Ts65Dn mouse model of Down syndrome.…”

Section: Modeling Ds Cognitive Impairmentmentioning

confidence: 86%

From Abnormal Hippocampal Synaptic Plasticity in Down Syndrome Mouse Models to Cognitive Disability in Down Syndrome

Cramer

Galdzicki

2012

Neural Plasticity

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Down syndrome (DS) is caused by the overexpression of genes on triplicated regions of human chromosome 21 (Hsa21). While the resulting physiological and behavioral phenotypes vary in their penetrance and severity, all individuals with DS have variable but significant levels of cognitive disability. At the core of cognitive processes is the phenomenon of synaptic plasticity, a functional change in the strength at points of communication between neurons. A wide variety of evidence from studies on DS individuals and mouse models of DS indicates that synaptic plasticity is adversely affected in human trisomy 21 and mouse segmental trisomy 16, respectively, an outcome that almost certainly extensively contributes to the cognitive impairments associated with DS. In this review, we will highlight some of the neurophysiological changes that we believe reduce the ability of trisomic neurons to undergo neuroplasticity-related adaptations. We will focus primarily on hippocampal networks which appear to be particularly impacted in DS and where consequently the majority of cellular and neuronal network research has been performed using DS animal models, in particular the Ts65Dn mouse. Finally, we will postulate on how altered plasticity may contribute to the DS cognitive disability.

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Section: Modeling Ds Cognitive Impairmentmentioning

confidence: 86%

From Abnormal Hippocampal Synaptic Plasticity in Down Syndrome Mouse Models to Cognitive Disability in Down Syndrome

Cramer

Galdzicki

2012

Neural Plasticity

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“…Of these models, Ts65Dn is most widely used and consists of a genomic fragment with 49% syntenic regions and 55% of the HSA21 gene orthologs triplicated [50, 51]. These mice have lower dendritic density, enlarged spine heads, as well as impaired hippocampal-dependent learning and memory, tested using the Morris water maze, as well as impaired LTP at excitatory hippocampal synapses [52–55], yet enhanced LTD [56, 57]. Ongoing research in DS has focused on creating mouse models with smaller selections of trisomic genes included in the DS critical region.…”

Section: Spine Dysgenesis In Autism Related Disordersmentioning

confidence: 99%

Dendritic spine dysgenesis in autism related disorders

Phillips

Pozzo-Miller

2015

Neuroscience Letters

164

133

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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.

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“…In fact, some studies have attempted to reverse the cognitive impairments observed in Ts65Dn mice by using GABAA [28] or GABAB [27] receptor antagonists, obtaining promising results. Another way to act over the system was blocking NMDA receptors using memantine, reflecting that the problem is more complex that just over-inhibition [29].…”

Section: Introductionmentioning

confidence: 99%

Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

et al. 2014

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Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration producing intellectual disability. We have used the Ts65Dn model, that mimics some of the alterations observed in Down Syndrome. This genetic alteration induces an imbalance between excitation and inhibition that has been suggested as responsible for the cognitive impairment present in this syndrome. The hippocampus has a crucial role in memory processing and is an important area to analyze this imbalance. In this report we have analysed, in the hippocampus of Ts65Dn mice, the expression of synaptic markers: synaptophysin, vesicular glutamate transporter-1 and isoform 67 of the glutamic acid decarboxylase; and of different subtypes of inhibitory neurons (Calbindin D-28k, parvalbumin, calretinin, NPY, CCK, VIP and somatostatin). We have observed alterations in the inhibitory neuropil in the hippocampus of Ts65Dn mice. There was an excess of inhibitory puncta and a reduction of the excitatory ones. In agreement with this observation, we have observed an increase in the number of inhibitory neurons in CA1 and CA3, mainly interneurons expressing calbindin, calretinin, NPY and VIP, whereas parvalbumin cell numbers were not affected. These alterations in the number of interneurons, but especially the alterations in the proportion of the different types, may influence the normal function of inhibitory circuits and underlie the cognitive deficits observed in DS.

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Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine

Cited by 41 publications

References 38 publications

From Abnormal Hippocampal Synaptic Plasticity in Down Syndrome Mouse Models to Cognitive Disability in Down Syndrome

From Abnormal Hippocampal Synaptic Plasticity in Down Syndrome Mouse Models to Cognitive Disability in Down Syndrome

Dendritic spine dysgenesis in autism related disorders

Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

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