Neurodegenerative Diseases

Micromolar concentrations of glutamate, acting at non-NMDA, kainatepreferring receptors, increased the survival of cultured mouse hippocampal neurons maintained in serum-free, chemically-defined medium. Glutamate in excess of 20 11M was excitotoxic. Thus, the survival versus glutamate dose response relation was bellshaped with an optimal glutamate concentration near 111M. Hippocampal neurons from mice with the genetic defect, trisomy 16 (Ts16), died 2-3 times faster than normal (euploid) neurons. Moreover, glutamate, at all concentrations tested, failed to increase survival of Ts16 neurons. Ts16 is a naturally-occurring mouse genetic abnormality, the human analog of which (Down syndrome) leads to altered brain development and Alzheimer's disease. These results demonstrate that the Ts16 genotype confers a defect in the glutamate-mediated survival response of hippocampal neurons and that this defect can account for their accelerated death.

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