ALTERED CA2-NEURONS OF TRISOMY-16 MICE - A MODEL OF DOWNS-SYNDROME( SIGNALING AND MITOCHONDRIAL DEFICIENCIES IN HIPPOCAMPAL)

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.