Selective impairment of long-term depression in accumbal D1-MSNs involves calcium-permeable AMPARs in Alzheimer's disease
Alzheimers 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; however, the synaptic mechanisms underlying this vulnerability remain unclear. Here, we identify a cell-type-specific synaptic mechanism in the nAc linking early intraneuronal A{beta} accumulation to circuit dysfunction. Using a double transgenic APP/PS1 mouse model expressing tdTomato in dopamine D1 receptor-positive medium spiny neurons (D1R+ MSNs), we show that long-term depression (LTD) is selectively impaired in D1R+ MSNs despite comparable A{beta} levels across neuronal subtypes, revealing differential functional vulnerability. This deficit is associated with an increased contribution of calcium-permeable AMPA receptors (CP-AMPARs) and a disruption of mGluR1/5-dependent LTD, a key mechanism regulating AMPAR trafficking. Pharmacological blockade of CP-AMPARs restores synaptic depression, indicating altered receptor composition as a central feature of this phenotype. These synaptic alterations co-occur with reduced dopaminergic signaling and selective behavioral changes characterized by increased consumption of palatable reward and altered baseline context preference, while associative learning remains preserved. Together, these findings reveal a postsynaptic mechanism in which impaired mGluR-dependent plasticity permits persistent CP-AMPAR signaling, shifting synaptic balance toward increased excitatory drive and mesolimbic hyperactivity in AD.