Amyloid-β oligomers in the nucleus accumbens decrease motivation via insertion of calcium-permeable AMPA receptors

• Published in: Molecular psychiatry Vol. 27; no. 4; pp. 2146 - 2157
• Main Authors: Guo, Changyong, Wen, Di, Zhang, Yihong, Mustaklem, Richie, Mustaklem, Basil, Zhou, Miou, Ma, Tao, Ma, Yao-Ying
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2022; Nature Publishing Group
• Subjects: 14/19; 14/32; 14/34; 631/337; 631/378; 64/60; 692/699/476/1414; 9/74; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Behavioral Sciences; Biological Psychology; Calcium - metabolism; Calcium permeability; Emotional behavior; Humans; Medicine; Medicine & Public Health; Mental disorders; Motivation; Neurodegeneration; Neurodegenerative diseases; Neurosciences; Nucleus accumbens; Nucleus Accumbens - metabolism; Oligomers; Pharmacotherapy; Psychiatry; Quality of life; Receptors, AMPA - metabolism; Receptors, Calcium-Sensing; Synapses - metabolism; Synaptic transmission; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; β-Amyloid
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-022-01459-0

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.