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The Journal of Neuroscience, September 15, 1998, 18(18):7216-7231

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

Sebastian Schuchmann, Wolfgang Müller, and Uwe Heinemann

Department of Neurophysiology, Institute of Physiology, Charité, Humboldt University Berlin, D-10117 Berlin, Germany

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 Ca²⁺ 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, [Ca²⁺]_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 [Ca²⁺]_i levels were elevated in Ts16 neurons. Moreover, in comparison to diploid neurons, Ts16 neurons showed a prolonged recovery of [Ca²⁺]_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 Ca²⁺ impairs mitochondrial energy metabolism and may play a role in the pathogenesis of neurodegenerative changes in neurons from Ts16 mice.

Key words: trisomy 16; Down's syndrome; Alzheimer's disease; hippocampal culture; calcium; mitochondrial membrane potential; NAD(P)H

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18187216-16$05.00/0

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