Altered signaling pathways underlying abnormal hippocampal synaptic plasticity in the Ts65Dn mouse model of Down syndrome

Siarey, Richard J.; Kline-Burgess, Angelina; Cho, Madelaine; Balbo, Andrea; Best, Tyler K.; Harashima, Chie; Klann, Eric; Galdzicki, Zygmunt

doi:10.1111/j.1471-4159.2006.04238.x

Cited by 11 publications

(13 citation statements)

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“…Numerous studies have demonstrated that TS mice present altered hippocampal synaptic plasticity that correlates with their cognitive alterations. In agreement with previous evidence , the present study showed that LTP was reduced in TS mice, and melatonin treatment for 5–6 months completely rescued LTP in the CA1 area in trisomic animals. Consistent with these findings, chronic melatonin treatment has been shown to rescue deficits in hippocampal LTP and spatial memory after intra‐hippocampal injection of A β , although the acute application of melatonin directly to mouse and rat hippocampal slices inhibits LTP in the CA1 region .…”

Section: Discussionsupporting

confidence: 93%

“…Adult hippocampal neurogenesis has an important role in the establishment of hippocampal long‐term potentiation (LTP) , which is considered to be the electrophysiological substrate of learning and memory . TS mice show a marked reduction in LTP in the CA1 and DG areas that correlates with their cognitive deficits .…”

Section: Introductionmentioning

confidence: 99%

“…One of the mechanisms proposed to underlie this altered synaptic plasticity in TS animals is enhanced inhibition due to an imbalance between excitatory and inhibitory neurotransmission. TS mice have increased GABA‐mediated inhibition and a concomitant decrease in glutamatergic transmission resulting in impaired hippocampal LTP . Different pharmacological manipulations that restore or improve the balance between excitatory and inhibitory transmission rescue neural plasticity and cognitive abilities in the TS mouse model of DS .…”

Section: Introductionmentioning

confidence: 99%

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Chronic melatonin treatment rescues electrophysiological and neuromorphological deficits in a mouse model ofDown syndrome

Corrales

Vidal

García

et al. 2013

Journal of Pineal Research

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The Ts65Dn mouse (TS), the most commonly used model of Down syndrome (DS), exhibits several key phenotypic characteristics of this condition. In particular, these animals present hypocellularity in different areas of their CNS due to impaired neurogenesis and have alterations in synaptic plasticity that compromise their cognitive performance. In addition, increases in oxidative stress during adulthood contribute to the age-related progression of cognitive and neuronal deterioration. We have previously demonstrated that chronic melatonin treatment improves learning and memory and reduces cholinergic neurodegeneration in TS mice. However, the molecular and physiological mechanisms that mediate these beneficial cognitive effects are not yet fully understood. In this study, we analyzed the effects of chronic melatonin treatment on different mechanisms that have been proposed to underlie the cognitive impairments observed in TS mice: reduced neurogenesis, altered synaptic plasticity, enhanced synaptic inhibition and oxidative damage. Chronic melatonin treatment rescued both impaired adult neurogenesis and the decreased density of hippocampal granule cells in trisomic mice. In addition, melatonin administration reduced synaptic inhibition in TS mice by increasing the density and/or activity of glutamatergic synapses in the hippocampus. These effects were accompanied by a full recovery of hippocampal LTP in trisomic animals. Finally, melatonin treatment decreased the levels of lipid peroxidation in the hippocampus of TS mice. These results indicate that the cognitive-enhancing effects of melatonin in adult TS mice could be mediated by the normalization of their electrophysiological and neuromorphological abnormalities and suggest that melatonin represents an effective treatment in retarding the progression of DS neuropathology.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Chronic melatonin treatment rescues electrophysiological and neuromorphological deficits in a mouse model ofDown syndrome

Corrales

Vidal

García

et al. 2013

Journal of Pineal Research

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“…; Siarey et al . ). Several mechanisms are thought to mediate the excitatory–inhibitory imbalance, namely, the decreased numbers of excitatory synapses, excessive GABA drive as a result of higher synaptic vesicle release probability, and/or increased number of inhibitory interneurons in the neocortex and hippocampus (Chowdhury et al .…”

Section: Synapse Dysfunction In Neurodevelopmental Disordersmentioning

confidence: 97%

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Lepeta

Lourenco

Schweitzer

et al. 2016

Journal of Neurochemistry

296

220

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Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in diseaseassociated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders.

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“…Ts65Dn mice have enhanced long-term depression (LTD) and reduced NMDA receptor-dependent long-term plasticity (LTP) of synapses in the CA1 region of the hippocampus 27,32–38. Signaling molecules involved in the induction of LTP are also disrupted in the hippocampus of Ts65Dn mice 39. Based on these anatomical and physiological studies, therapeutic strategies have been described that rescue LTP and deficits in hippocampal-dependent behavior.…”

Section: Neurodevelopmental Disordersmentioning

confidence: 99%

Emerging Pharmacotherapies for Neurodevelopmental Disorders

Wetmore

Garner

2010

Journal of Developmental &Amp; Behavioral Pediatrics

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A growing and interdisciplinary translational neuroscience research effort for neurodevelopmental disorders (NDDs) is investigating the mechanisms of dysfunction and testing effective treatment strategies in animal models and, when possible, in the clinic. NDDs with a genetic basis have received particular attention. Transgenic animals that mimic genetic insults responsible for disease in man have provided insight about mechanisms of dysfunction, and, surprisingly, have shown that cognitive deficits can be addressed in adult animals. This review will present recent translational research based on animal models of genetic NDDs, as well as pharmacotherapeutic strategies under development to address deficits of brain function for Down syndrome, fragile X syndrome, Rett syndrome, neurofibromatosis-1, tuberous sclerosis, and autism. Although these disorders vary in underlying causes and clinical presentation, common pathways and mechanisms for dysfunction have been observed. These include abnormal gene dosage, imbalance among neurotransmitter systems, and deficits in the development, maintenance and plasticity of neuronal circuits. NDDs affect multiple brain systems and behaviors that may be amenable to drug therapies that target distinct deficits. A primary goal of translational research is to replace symptomatic and supportive drug therapies with pharmacotherapies based on a principled understanding of the causes of dysfunction. Based on this principle, several recently developed therapeutic strategies offer clear promise for clinical development in man.

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Altered signaling pathways underlying abnormal hippocampal synaptic plasticity in the Ts65Dn mouse model of Down syndrome

Cited by 11 publications

References 0 publications

Chronic melatonin treatment rescues electrophysiological and neuromorphological deficits in a mouse model ofDown syndrome

Chronic melatonin treatment rescues electrophysiological and neuromorphological deficits in a mouse model ofDown syndrome

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Emerging Pharmacotherapies for Neurodevelopmental Disorders

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