Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome

Fernandez, Fabian-Xosé; Morishita, Wade; Zuniga, Elizabeth; Nguyen, James; Blank, Martina; Malenka, Robert C.; Garner, Craig C.

doi:10.1038/nn1860

Cited by 477 publications

(501 citation statements)

References 14 publications

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“…Moreover, our findings support recent studies in humans and rodent models linking hippocampal overactivity and hyperexcitability to age-related memory deficits (Koh et al 2010;Bakker et al 2012;Davis et al 2014) and are consistent with the correlation of hippocampal overactivity with memory deficits in schizophrenia (Tregellas et al 2014). However, hippocampal neural disinhibition may facilitate hippocampal synaptic plasticity and, thereby, improve memory, if such disinhibition is finely and dynamically regulated by endogenous plasticity (Donato et al 2013) or if there is a pre-existing deficit due to increased neural inhibition (Fernandez et al 2007). …”

Section: Memory Deficitssupporting

confidence: 90%

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

et al. 2016

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Section: Memory Deficitssupporting

confidence: 90%

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

et al. 2016

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“…Altogether, these results suggest an unbalanced level of inhibitory and excitatory inputs in the neocortex and the hippocampus in DS. Supporting this fact, an overactivation of the inhibitory system causing a general inhibition in the brain has been observed in Ts65Dn mice (Fernandez et al 2007). This increased inhibition may be responsible, at least to some extent, for the cognitive impairment observed in DS.…”

Section: Introductionmentioning

confidence: 77%

Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

et al. 2010

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Down's syndrome (DS), with an incidence of one in 800 live births, is the most common genetic disorder associated with mental retardation. This trisomy on chromosome 21 induces a variable phenotype in which the only common feature is the presence of mental retardation. The neural mechanisms underlying mental retardation might include defects in the formation of neuronal networks and neural plasticity. DS patients have alterations in the morphology, the density and the distribution of dendritic spines in the pyramidal neurons of the cortex. Our hypothesis is that the deficits in dendritic arborization observed in the principal neurons of DS patients and Ts65Dn mice (a model for DS that mimics most of the structural alterations observed in humans) may be mediated to some extent by changes in their inhibitory inputs. Different types of interneurons control different types of inhibition. Therefore, to understand well the changes in inhibition in DS, it is necessary to study the different types of interneurons separately. We have studied the expression of synaptophysin, Glutamic acid decarboxylase-67 (GAD-67) and calcium-binding protein-expressing cells in the primary somatosensory cortex of 4-5 month old Ts65Dn mice. We have observed an increment of GAD67 immunoreactivity that is related mainly to an increment of calretinin-immunoreactive cells and among them the ones with bipolar morphology. Since there is a propensity for epilepsy in DS patients, this increase in interneurons might reflect an attempt by the system to block overexcitation rather than an increment in total inhibition and could explain the deficit in interneurons and principal cells observed in elderly DS patients.

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“…Thus, the relationship between ACh release and performance is imperfect and may well reflect other consequences of age such as additive dysfunctions and compensatory changes within cholinergic systems. In addition, the imperfect association of ACh markers with behavior may also reflect independent consequences of age in the partial trisomy mice, for example in other neurotransmitters (Fernandez et al, 2007) or neurobiological processes. These other processes include impaired long-term potentiation (Costa and Grybko, 2005;Fernandez et al, 2007;Kleschevnikov et al, 2004;Siarey et al, 1997), enhanced long-term depression (Siarey et al, 1999), impaired expression of brainderived neurotrophic factor (Seo and Isacson, 2005), altered signaling pathways (Siarey et al, 2006), and altered neuroanatomical organization of the hippocampus Hanson et al, 2007;Kurt et al, 2004;Lorenzi and Reeves, 2006).…”

Section: General Conclusionmentioning

confidence: 99%

“…Spontaneous alternation scores decrease in aged rodents (McNay and Gold, 2001;Stone, Rudd and Gold, 1992) and age-related and other impairments can be reversed by pharmacological agents including cholinergic agonists (Gold, , 2007McNay and Gold, 2001;Sarter et al, 1988). In addition, there is recent evidence that Ts65Dn mice exhibit deficits on this task (Fernandez et al, 2007). Thus, spontaneous alternation tasks provide opportunities to assess age-related impairments and pharmacological reversals of those impairments in Ts65Dn mice.…”

Section: Introductionmentioning

confidence: 99%

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

Chang

Gold

2008

Neurobiology of Learning and Memory

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Spatial working memory and the ability of a cholinesterase inhibitor to enhance memory were assessed at 4, 10, and 16 months of ages in control and Ts65Dn mice, a partial trisomy model of Down syndrome, with possibly significant relationships to Alzheimer's Disease as well. In addition, ACh release during memory testing was measured in samples collected from the hippocampus using in vivo microdialysis at 4, 10, and 22-25 months of age. When tested on a four-arm spontaneous alternation task, the Ts65Dn mice exhibited impaired memory scores at both 4 and 10 months. At 16 months, control performance had declined toward that of the Ts65Dn mice and the difference in scores across genotypes was not significant. Physostigmine (50 μg/kg) fully reversed memory deficits in the Ts65Dn mice in the 4-month-old group but not in older mice. Ts65Dn and control mice exhibited comparable baseline levels of ACh release at all ages tested; these levels did not decline significantly across age in either genotype. ACh release increased significantly during alternation testing only in the young Ts65Dn and control mice. However, the increase in ACh release during alternation testing was significantly greater in control than Ts65Dn mice at this age. The controls exhibited a significant age-related decline in the testing-related increase in ACh release. With only a small increase during testing in young Ts65Dn mice, the age-related decline in responsiveness of ACh release to testing was not significant in these mice. Overall, these results suggest that diminished responsiveness of ACh release in the hippocampus to behavioral testing may contribute memory impairments in Ts65Dn mice.

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Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome

Cited by 477 publications

References 14 publications

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

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