Abstract
Our recent investigation revealed that deficiency of N-methyl-D-aspartate (NMDA) receptor subunit GluN3A (NR3A) is a trigger for chronic neuronal hyperactivity and disruptionFfepspof Ca(2+) homeostasis, leading to sporadic Alzheimer's disease (AD) phenotypes. The identification of the amyloid-independent pathogenesis was a surprise considering that GluN3A is a much less known NMDA receptor subunit with obscure function in aging adulthood, while the new concept of degenerative excitotoxicity as a decade-long pathogenic mechanism of AD/dementia remains to be further delineated. With negative observations in GRIN3A-/- mouse, Verhaeghe et al. in their letter challenge the "odd" idea that lasting GluN3A deficiency is detrimental and responsible for the spontaneous progression of AD and cognitive decline. We now discuss the potential mouse strain hypothesis and experimental data in these two investigations, and provide additional evidence that further supports the validity and specificity of GluN3A deficiency in the development of AD and associated dementia.