Altered Ca²⁺Signaling and Mitochondrial Deficiencies in Hippocampal Neurons of Trisomy 16 Mice: A Model of Down’s Syndrome

Abstract

It has been suggested that augmented nerve cell death in neurodegenerative diseases might result from an impairment of mitochondrial function. To test this hypothesis, we investigated age-dependent changes in neuronal survival and glutamate effects on Ca 2ϩ homeostasis and mitochondrial energy metabolism in cultured hippocampal neurons from diploid and trisomy 16 (Ts16) mice, a model of Down's syndrome. Microfluorometric techniques were used to measure survival rate, [Ca 2ϩ ] i level, mitochondrial membrane potential, and NAD(P)H autofluorescence. We found that Ts16 neurons die more than twice as fast as diploid neurons under otherwise identical culture conditions. Basal [Ca 2ϩ ] i levels were elevated in Ts16 neurons. Moreover, in comparison to diploid neurons, Ts16 neurons showed a prolonged recovery of [Ca 2ϩ ] i and mitochondrial membrane potential after brief glutamate application. Glutamate evoked an initial NAD(P)H decrease that was found to be extended in Ts16 neurons in comparison to diploid neurons. Furthermore, for all age groups tested, glutamate failed to cause a subsequent NAD(P)H overshoot in Ts16 cultures in contrast to diploid cultures. In the presence of cyclosporin A, an inhibitor of the mitochondrial membrane permeability transition, NAD(P)H increase was observed in both diploid and Ts16 neurons. The results support the hypothesis that Ca 2ϩ impairs mitochondrial energy metabolism and may play a role in the pathogenesis of neurodegenerative changes in neurons from Ts16 mice.

THIS ARTICLE HAS BEEN RETRACTED: Diminished Glutathione Levels Cause Spontaneous and Mitochondria‐Mediated Cell Death in Neurons from Trisomy 16 Mice:

“…Both increased intracellular Ca 2ϩ and ROS concentrations have solely or in conjunction been demonstrated to amplify the sensitivity of the mitochondrial permeability transition (Bernardi, 1996;Kowaltowski et al, 1996;Scanlon and Reynolds, 1998). Cyclosporin A-sensitive glutamate-induced activation of the mitochondrial permeability transition leads to uncoupling of oxidative phosphorylation, release of mitochondrial glutathione, impaired mitochondrial energy metabolism, and mitochondrial swelling (Savage and Reed, 1994;Schuchmann et al, 1998). Furthermore, activation of the mitochondrial permeability transition has been reported to constitute a critical early event in the process of programmed cell death (Zamzami et al, 1995(Zamzami et al, , 1996.…”

“…In contrast, the ␤-amyloid precursor protein product, ␤-amyloid protein, demonstrated to occur in Ts16 hippocampal neurons (Richards et al, 1991), is suspected to render neurons more vulnerable to excitotoxicity (Mattson et al, 1992). We have previously demonstrated altered Ca 2ϩ signaling and mitochondrial deficiencies in cultured hippocampal Ts16 neurons (Schuchmann et al, 1998). …”

Down syndrome with and without dementia: An in vivo proton Magnetic Resonance Spectroscopy study with implications for Alzheimer's disease

“…Indirectly, mI may affect neuronal function via a cascade of secondary changes at different levels of the signal transduction process and gene expression in the central nervous system. In addition, mI is a precursor to key phospholipids involved in calcium concentrations in brain and so may indirectly effect Ca 2+ homeostasis (Yao et al, 2000); a process already implicated in the neurotoxic cascade of DS (Schuchmann et al, 1998) as well as AD (Emilsson et al, 2006). While increased [mI] may independently increase the risk for dementia, we suggest that it is more likely [mI] combines with other risk factors in DS (e.g., trisomy of the APP gene and/ or hippocampal atrophy) to act as a synergistic mechanism for dementia in this vulnerable population.…”

Live imaging of neuronal connections by magnetic resonance: Robust transport in the hippocampal–septal memory circuit in a mouse model of Down syndrome

“…radioactive or fluorescent) used to study neuronal projections. In addition to transport defects, DS mice may also have synaptic alterations that could effect Mn 2+ uptake (Schuchmann et al, 1998.…”