S. Schuchmann et al., ALTERED CA2-NEURONS OF TRISOMY-16 MICE - A MODEL OF DOWNS-SYNDROME( SIGNALING AND MITOCHONDRIAL DEFICIENCIES IN HIPPOCAMPAL), The Journal of neuroscience, 18(18), 1998, pp. 7216-7231
It has been suggested that augmented nerve cell death in neurodegenera
tive diseases might result from an impairment of mitochondrial functio
n. To test this hypothesis, we investigated age-dependent changes in n
euronal survival and glutamate effects on Ca2+ homeostasis and mitocho
ndrial energy metabolism in cultured hippocampal neurons from diploid
and trisomy 16(Ts16) mice, a model of Down's syndrome. Microfluorometr
ic techniques were used to measure survival rate, [Ca2+](i) level, mit
ochondrial 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 e
levated in Ts16 neurons. Moreover, in comparison to diploid neurons, T
s16 neurons showed a prolonged recovery of [Ca2+](i) and mitochondrial
membrane potential after brief glutamate application. Glutamate evoke
d an initial NAD(P)H decrease that was found to be extended in Ts16 ne
urons in comparison to diploid neurons. Furthermore, for all age group
s tested, glutamate failed to cause a subsequent NAD(P)H overshoot in
Ts16 cultures in contrast to diploid cultures. In the presence of cycl
osporin A, an inhibitor of the mitochondrial membrane permeability tra
nsition, NAD(P)H increase was observed in both diploid and Ts16 neuron
s. The results support the hypothesis that Ca2+ impairs mitochondrial
energy metabolism and may play a role in the pathogenesis of neurodege
nerative changes in neurons from Ts16 mice.