Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse

Topic: Brain proteins, microglia and lab models

The survival of cultured mouse hippocampal neurons was found to be greatly enhanced by micromolar concentrations of the excitatory neurotransmitter glutamate. Blockade of kainate/AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptors increased the rate of neuron death, suggesting that endogenous glutamate in the cultures promotes survival. Addition of glutamate (0.5-1 microM) further increased neuron survival, whereas glutamate in excess of 20 microM resulted in increased death. Thus, the survival vs. glutamate dose-response relation is bell-shaped with an optimal glutamate concentration near 1 microM. We found that 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. In contrast, the neurotrophic polypeptide basic fibroblast growth factor did increase the survival of Ts16 and euploid neurons. Ts16 is a naturally occurring mouse genetic abnormality, the human analog of which (Down syndrome) leads to altered brain development and Alzheimer 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 contribute to their accelerated death.

@article{bambrick1995-7568199,
  author  = {Bambrick, L. L. and Yarowsky, P. J. and Krueger, B. K.},
  title   = {{Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse}},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year    = {1995},
  doi     = {10.1073/pnas.92.21.9692},
  pmid    = {7568199},
  url     = {https://doi.org/10.1073/pnas.92.21.9692}
}

Key findings

• Blockade of kainate/AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptors increased the rate of neuron death, suggesting that endogenous glutamate in the cultures promotes survival.
• We found that hippocampal neurons from mice with the genetic defect trisomy 16 (Ts16) died 2-3 times faster than normal (euploid) neurons.
• These results demonstrate that the Ts16 genotype confers a defect in the glutamate-mediated survival response of hippocampal neurons and that this defect can contribute to their accelerated death.

Why it matters

In cultured mouse hippocampal neurons, glutamate at low concentrations helped neurons survive, but hippocampal neurons from mice with the trisomy 16 genetic defect died 2-3 times faster than normal and did not respond to glutamate at any concentration. This is a cell-culture and animal study, so it does not show a treatment for Alzheimer's disease in people.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1073/pnas.92.21.9692
• PubMed: 7568199
• Original source →
• Free full text: PubMed Central →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Mouse model of neurodegeneration: atrophy of basal forebrain cholinergic neurons in trisomy 16 transplants Proceedings of the National Academy of Sciences of the United States of America · 1992-02-01 · usefulness score 38/100 · Down syndrome and Alzheimer's

Later studies that cite this one

1 study in the alzhub library lists this one in its references.

• Long-term basal forebrain cholinergic-rich grafts derived from trisomy 16 mice do not develop beta-amyloid pathology and neurodegeneration but demonstrate neuroinflammatory responses International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience · 1998-11-01 · usefulness score 29/100 · Down syndrome and Alzheimer's

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