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

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 (c-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 ,uM) further increased neuron survival, whereas glutamate in excess of20 ,iM resulted in increased death. Thus, the survival vs. glutamate dose-response relation is bell-shaped with an optimal glutamate concentration near 1 IzM. 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 ofhippocampal neurons and that this defect can contribute to their accelerated death.The virtual absence of neurogenesis in the adult mammalian brain underscores the necessity of ensuring the survival of neurons over many years. Since it has been suggested that all cells require a constant trophic signal to block cell death (1), the loss of neurons associated with normal aging and the accelerated neuronal death characteristic of neurodegenerative disorders could result from the failure of one or more intrinsic survival mechanisms.Many agents have been shown to promote the survival of neurons. Polypeptide neurotrophic factors (2-5) include basic fibroblast growth factor (bFGF), glial cell line-derived neurotrophic factor, and the neurotrophins-e.g., nerve growth factor and brain-derived neurotrophic factor. Not all types of neurons respond to every neurotrophic factor, but many neurons respond to multiple factors, providing a redundancy of trophic inputs to ensure long-term neuron survival. Activation of excitatory amino acid receptors has also been shown to elicit a trophic response in neurons. Although very high concentrations of glutamate are toxic to most neurons (for review, see ref. 6), lower concentrations of glutamate or glutamate agonists have been reported to increase survival of postnatal cerebellar granule cells in vitro (7-9), while glutamate receptor (GluR) antagonists can decrease their survival (7). Similarly, metabotropic GluR activation has been found to promote the in vitro survival of cerebellar Purkinje and granule cells (10, 11). It has also been shown that in vivo treatment with N-methyl-D-aspartate (NMDA) GluR antagonists decreases the numbers of surviving granule cells in the developing dentate gyrus of the hippocampus (12), suggesting that endogenou...

THIS ARTICLE HAS BEEN RETRACTED: Diminished Glutathione Levels Cause Spontaneous and Mitochondria‐Mediated Cell Death in Neurons from Trisomy 16 Mice:

“…Previous studies showed reduced neuronal GSH levels and increased neuronal cell loss in hippocampal Ts16 cultures (Stabel-Burow et al, 1997). Furthermore, cultured hippocampal Ts16 neurons display an inherited defect in survival response mediated by glutamate in low concentrations (Bambrick et al, 1995) and show altered electrogenesis, possibly associated with augmented Ca 2ϩ loading (Galdzicki et al, 1993). In the Ts16 mice model, the ␤-amyloid precursor protein, important for the regu-R e t r a c t e d lation of intracellular Ca 2ϩ (Mattson et al, 1993), is overexpressed.…”

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

“…As with cytoskeletal protection, indirect modulation of the endocannabinoid system with AM374/AM404 produced the same or better synaptic protection compared with treatment with the CB 1 agonist. The protection of synaptic integrity would provide an added beneficial effect because the activity of glutamatergic synapses in the hippocampus is vital for neuronal maintenance (Bambrick et al, 1995;Bahr et al, 2002). Thus, the neuroprotective effects may have extended beyond the site at which AM374/AM404 was injected.…”

Biphasic Coupling of Neuronal Nitric Oxide Synthase Phosphorylation to the NMDA Receptor Regulates AMPA Receptor Trafficking and Neuronal Cell Death

“…Exposure to low concentrations of glutamate induces neuroprotective effects in dispersed neuronal cultures (Balazs et al, 1988;Bambrick et al, 1995;Hardingham et al, 2002;Jiang et al, 2005;Soriano et al, 2006). In contrast, high concentrations of glutamate trigger excitotoxicity in cultured neurons (Michaels and Rothman, 1990;Westbrook, 1993;Choi, 1994;Ankarcrona et al, 1995;Raymond et al, 1996).…”