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.

doi:10.64898/2026.01.19.700385

bioRxiv · 10.64898/2026.01.19.700385

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.

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Abstract

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.

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Riffo-Lepe, N., Gonzalez-Sanmiguel, J., Meza, I., Saavedra-Sieyes, P., Armijo-Weingart, L., Salinas, A., San Martin, L., Aguayo, L.. 2026-01-22. Selective impairment of long-term depression in accumbal D1-MSNs involves calcium-permeable AMPARs in Alzheimer's disease. https://doi.org/10.64898/2026.01.19.700385

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