Related Experiment Videos
Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse
L L Bambrick1, P J Yarowsky, B K Krueger
1Department of Physiology, University of Maryland School of Medicine, Baltimore 21201, USA.
Abstract:
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.
Insights
Glutamate enhances mouse hippocampal neuron survival in a dose-dependent manner. Genetic defects in trisomy 16 mice impair this glutamate response, leading to accelerated neuron death.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- The excitatory neurotransmitter glutamate plays a crucial role in neuronal function and survival.
- Glutamate receptors, specifically kainate/AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, are implicated in mediating neuronal responses.
- Trisomy 16 (Ts16) is a mouse model for Down syndrome, characterized by altered brain development.
Purpose of the Study:
- To investigate the role of glutamate in the survival of cultured mouse hippocampal neurons.
- To determine if hippocampal neurons from Ts16 mice exhibit altered responses to glutamate.
- To explore potential therapeutic targets for neuroprotection in Ts16-related neurological conditions.
Main Methods:
- Culturing mouse hippocampal neurons.
- Administering varying concentrations of glutamate to assess neuron survival.
- Utilizing kainate/AMPA receptor antagonists to block glutamate signaling.
- Comparing survival rates of neurons from Ts16 and euploid (normal) mice.
- Testing the effects of basic fibroblast growth factor on neuron survival.
Main Results:
- Micromolar concentrations of glutamate significantly enhanced hippocampal neuron survival, with an optimal concentration near 1 microM.
- Blocking kainate/AMPA receptors increased neuron death, indicating a role for endogenous glutamate in survival.
- Hippocampal neurons from Ts16 mice exhibited a 2-3 fold faster death rate compared to euploid neurons.
- Glutamate failed to enhance the survival of Ts16 neurons at any tested concentration.
- Basic fibroblast growth factor effectively increased the survival of both Ts16 and euploid neurons.
Conclusions:
- Hippocampal neuron survival is critically dependent on glutamate signaling in a bell-shaped dose-response curve.
- The Ts16 genotype confers a defect in the glutamate-mediated survival pathway.
- This glutamate response defect in Ts16 neurons contributes to their accelerated death and may be relevant to Down syndrome and Alzheimer disease.