Selective impairment of long-term depression in accumbal D1R+ MSNs involves calcium-permeable AMPARs in early Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is increasingly associated with early circuit dysfunction preceding cognitive decline, including neuronal hyperactivity and neuropsychiatric symptoms linked to mesolimbic pathways. The nucleus accumbens (NAc), a central regulator of reward and motivational processing, exhibits early alterations in excitation/inhibition balance in patients and experimental models, yet the synaptic mechanisms underlying its vulnerability remain unclear. Using a double transgenic APP/PS1 mice crossed with a Drd1a-tdTomato reporter line, we combined cell-type-specific electrophysiology, immunohistochemistry, ex vivo photometry, and behavioral assays. At a pre-plaque stage, intraneuronal Aβ accumulated in both dopamine D1 receptor-positive (D1R+) and D1R-negative medium spiny neurons (MSNs). Despite comparable Aβ levels, both high-frequency stimulation-induced long-term depression (LTD) and mGluR1/5-dependent LTD were selectively impaired in D1R+ MSNs. This vulnerability was accompanied by an increased contribution of calcium-permeable AMPA receptors (CP-AMPARs). Subsequent CP-AMPAR blockade reduced the residual evoked excitatory postsynaptic current that persisted after mGluR1/5 activation in APP/PS1 D1R+ MSNs. Because paired-pulse ratios remained unchanged, this residual response was consistent with a predominantly postsynaptic mechanism. These synaptic changes were accompanied by reduced evoked dopamine signaling, increased chocolate consumption, and altered baseline context preference, whereas standard pellet consumption, conditioned place preference, anxiety-like behavior, and social behavior were unchanged. These findings define a pre-plaque, cell-type-specific synaptic phenotype in male APP/PS1 mice in which impaired mGluR1/5-dependent plasticity and persistent CP-AMPAR signaling in D1R+ MSNs coincide with selective reward-related alterations.