Selective impairment of long-term depression in accumbal D1-MSNs involves calcium-permeable AMPARs in Alzheimer’s disease

Early neuropsychiatric symptoms in Alzheimer's disease emerge before cognitive decline, yet their synaptic basis remains poorly defined. Here we identify an early, cell-type-specific disruption of synaptic plasticity in the nucleus accumbens during pre-plaque stages of disease. In APP/PS1 mice, intracellular amyloid-beta accumulation is associated with a selective loss of mGluR1/5-dependent long-term depression in dopamine D1 receptor-expressing medium spiny neurons, despite comparable intracellular amyloid-beta levels across neuronal subtypes. This impairment is accompanied by aberrant postsynaptic remodeling characterized by functional accumulation of calcium-permeable AMPA receptors and increased excitatory drive. These synaptic alterations coincide with reduced dopamine-dependent signaling and selective changes in reward-related behavior, including altered hedonic consumption. Together, these findings identify an early vulnerability of the mesolimbic reward system and suggest that non-cognitive manifestations of Alzheimer's disease arise from circuit-level imbalance before plaque deposition.