Reduced Synaptic STIM2 Expression and Impaired Store-Operated Calcium Entry Cause Destabilization of Mature Spines in Mutant Presenilin Mice

• Fraction of mushroom spines is reduced in PS1-M146V KI FAD neurons
• STIM2-nSOC-mediated Ca2+ flux is necessary for mushroom spine stability
• STIM2-nSOC-CaMKII pathway is impaired in PS1-M146V KI, aging, and AD neurons
• STIM2 overexpression rescues mushroom spine deficiency in PS1-M146V KI neurons

SummaryMushroom dendritic spine structures are essential for memory storage, and the loss of mushroom spines may explain memory defects in Alzheimer’s disease (AD). Here we show a significant reduction in the fraction of mushroom spines in hippocampal neurons from the presenilin-1 M146V knockin (KI) mouse model of familial AD (FAD). The stabilization of mushroom spines depends on STIM2-mediated neuronal store-operated calcium influx (nSOC) and continuous activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII). We demonstrate that STIM2-nSOC-CaMKII pathway is compromised in KI neurons, in aging neurons, and in sporadic AD brains due to downregulation of STIM2 protein. We further establish that overexpression of STIM2 rescues synaptic nSOC, CaMKII activity, and mushroom spine loss in KI neurons. Our results identify STIM2-nSOC-CaMKII synaptic maintenance pathway as a novel potential therapeutic target for treatment of AD and age-related memory decline.