Selective impairment of long-term depression in accumbal D1-MSNs involves calcium-permeable AMPARs in Alzheimer's disease
Riffo-Lepe, N.; Gonzalez-Sanmiguel, J.; Meza, I.; Saavedra-Sieyes, P.; Armijo-Weingart, L.; Salinas, A.; San Martin, L.; Aguayo, L.
Show abstract
Early neuropsychiatric symptoms in Alzheimers 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 Alzheimers disease arise from circuit-level imbalance before plaque deposition.
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