ABSTRACT
In addition to nervous system, cardiovascular and respiratory systems are primarily affected in Down syndrome (DS). The Ts65Dn mouse model is widely used to recapitulate cognitive dysfunction in DS. While these mice consistently show failure in learning and memory along with functional and structural abnormalities in the hippocampal region, the underlying mechanisms behind cognitive dysfunction remain to be fully elucidated. Convergent evidence implicates chronic episodes of hypoxemia in cognitive dysfunction in people with DS. Using an infra-red detection system to assess oxygen saturation in free-moving mice, we assessed arterial blood oxygenation in both adolescent and adult Ts65Dn mice and found a significant increase in the incidence of hypoxemia in both groups. Notably, the severity of hypoxemia increased during the dark cycle, suggesting a link between hypoxemia and increased motor activity. Postmortem analysis showed significant increase in the expression of mitochondrial Cox4i2, the terminal enzyme of the mitochondrial respiratory chain and oxygen response element. Altogether these data suggest early and chronic occurrence of hypoxemia in the Ts65Dn mouse model of DS, which can contribute to cognitive dysfunction in these mice.
Subject(s)
Down Syndrome/blood , Down Syndrome/enzymology , Hypoxia/blood , Hypoxia/enzymology , Oxygen/blood , Age Factors , Animals , Darkness , Dentate Gyrus/enzymology , Down Syndrome/genetics , Electron Transport Complex IV/genetics , Electron Transport Complex IV/metabolism , Mice, Mutant Strains , Mitochondria/enzymology , Protein Subunits/genetics , Protein Subunits/metabolismABSTRACT
BACKGROUND: Down syndrome is associated with significant failure in cognitive function. Our previous investigation revealed age-dependent degeneration of locus coeruleus, a major player in contextual learning, in the Ts65Dn mouse model of Down syndrome. We studied whether drugs already available for use in humans can be used to improve cognitive function in these mice. METHODS: We studied the status of ß adrenergic signaling in the dentate gyrus of the Ts65Dn mouse model of Down syndrome. Furthermore, we used fear conditioning to study learning and memory in these mice. Postmortem analyses included the analysis of synaptic density, dendritic arborization, and neurogenesis. RESULTS: We found significant atrophy of dentate gyrus and failure of ß adrenergic signaling in the hippocampus of Ts65Dn mice. Our behavioral analyses revealed that formoterol, a long-acting ß2 adrenergic receptor agonist, caused significant improvement in the cognitive function in Ts65Dn mice. Postmortem analyses revealed that the use of formoterol was associated with a significant improvement in the synaptic density and increased complexity of newly born dentate granule neurons in the hippocampus of Ts65Dn mice. CONCLUSIONS: Our data suggest that targeting ß2 adrenergic receptors is an effective strategy for restoring synaptic plasticity and cognitive function in these mice. Considering its widespread use in humans and positive effects on cognition in Ts65Dn mice, formoterol or similar ß2 adrenergic receptor agonists with ability to cross the blood brain barrier might be attractive candidates for clinical trials to improve cognitive function in individuals with Down syndrome.
Subject(s)
Adrenergic beta-2 Receptor Agonists/therapeutic use , Dendrites/drug effects , Down Syndrome/drug therapy , Ethanolamines/pharmacology , Ethanolamines/therapeutic use , Adrenergic beta-Antagonists/pharmacology , Adrenergic beta-Antagonists/therapeutic use , Animals , Cell Proliferation/drug effects , Dendrites/metabolism , Dendrites/ultrastructure , Disease Models, Animal , Doublecortin Domain Proteins , Down Syndrome/pathology , Fibroblast Growth Factor 2/genetics , Fibroblast Growth Factor 2/metabolism , Formoterol Fumarate , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Hippocampus/pathology , Hippocampus/ultrastructure , Humans , Male , Mice , Mice, Transgenic , Microtubule-Associated Proteins/metabolism , Nadolol/pharmacology , Neurons/pathology , Neuropeptides/metabolism , Receptors, Adrenergic, beta-2/metabolism , Synaptophysin/metabolismABSTRACT
Extensive neuropathological studies have established a compelling link between abnormalities in structure and function of subcortical monoaminergic (MA-ergic) systems and the pathophysiology of Alzheimer's disease (AD). The main cell populations of these systems including the locus coeruleus, the raphe nuclei, and the tuberomamillary nucleus undergo significant degeneration in AD, thereby depriving the hippocampal and cortical neurons from their critical modulatory influence. These studies have been complemented by genome wide association studies linking polymorphisms in key genes involved in the MA-ergic systems and particular behavioral abnormalities in AD. Importantly, several recent studies have shown that improvement of the MA-ergic systems can both restore cognitive function and reduce AD-related pathology in animal models of neurodegeneration. This review aims to explore the link between abnormalities in the MA-ergic systems and AD symptomatology as well as the therapeutic strategies targeting these systems. Furthermore, we will examine possible mechanisms behind basic vulnerability of MA-ergic neurons in AD.
Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , Dopamine/metabolism , Neurons/metabolism , Serotonin/metabolism , Alzheimer Disease/pathology , Brain/pathology , Humans , Neural Pathways/metabolism , Neural Pathways/pathology , Neurons/pathologyABSTRACT
BACKGROUND: There has been some difficulty getting standard laboratory rats to voluntarily consume large amounts of ethanol without the use of initiation procedures. It has previously been shown that standard laboratory rats will voluntarily consume high levels of ethanol if given intermittent-access to 20% ethanol in a 2-bottle-choice setting [Wise, Psychopharmacologia 29 (1973), 203]. In this study, we have further characterized this drinking model. METHODS: Ethanol-naïve Long-Evans rats were given intermittent-access to 20% ethanol (three 24-hour sessions per week). No sucrose fading was needed and water was always available ad libitum. Ethanol consumption, preference, and long-term drinking behaviors were investigated. Furthermore, to pharmacologically validate the intermittent-access 20% ethanol drinking paradigm, the efficacy of acamprosate and naltrexone in decreasing ethanol consumption were compared with those of groups given continuous-access to 10 or 20% ethanol, respectively. Additionally, ethanol consumption was investigated in Wistar and out-bred alcohol preferring (P) rats following intermittent-access to 20% ethanol. RESULTS: The intermittent-access 20% ethanol 2-bottle-choice drinking paradigm led standard laboratory rats to escalate their ethanol intake over the first 5 to 6 drinking sessions, reaching stable baseline consumption of high amounts of ethanol (Long-Evans: 5.1 +/- 0.6; Wistar: 5.8 +/- 0.8 g/kg/24 h, respectively). Furthermore, the cycles of excessive drinking and abstinence led to an increase in ethanol preference and increased efficacy of both acamprosate and naltrexone in Long-Evans rats. P-rats initiate drinking at a higher level than both Long-Evans and Wistar rats using the intermittent-access 20% ethanol paradigm and showed a trend toward a further escalation in ethanol intake over time (mean ethanol intake: 6.3 +/- 0.8 g/kg/24 h). CONCLUSION: Standard laboratory rats will voluntarily consume ethanol using the intermittent-access 20% ethanol drinking paradigm without the use of any initiation procedures. This model promises to be a valuable tool in the alcohol research field.
