It is essential to identify the neuronal mechanisms of Alzheimer’s Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to display AD-associated pathological changes in human cases. We found that the synaptic calcium permeable (CP)-AMPA receptors (AMPARs), which are normally absent in the NAc, can be revealed by acute exposure to Aβ oligomers (AβOs), and play a critical role in the emergence of synaptic loss and motivation deficits. Blockade of NAc CP-AMPARs can effectively prevent AβO-induced downsizing and pruning of spines and silencing of excitatory synaptic transmission. We conclude that AβO-triggered synaptic insertion of CP-AMPARs is a key mechanism mediating synaptic degeneration in AD, and preserving synaptic integrity may prevent or delay the onset of AD-associated psychiatric symptoms.
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This work was supported by NIH grants (R01AA025784, R01AG072897, and R21NS108128).
The authors declare no competing interests.
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Guo, C., Wen, D., Zhang, Y. et al. Amyloid-β oligomers in the nucleus accumbens decrease motivation via insertion of calcium-permeable AMPA receptors. Mol Psychiatry 27, 2146–2157 (2022). https://doi.org/10.1038/s41380-022-01459-0