Dopamine D3 receptor blockade restores hippocampal synaptic plasticity and rescues memory deficits in Alzheimer's disease mouse models.

Authors

Maria Rosaria Tropea, Giuseppe Aceto, Roberta Carmela Trovato, Emanuele Nicitra, Nicole Santuccio, Giorgia Intili, Marcello D'Ascenzo, Daniela Puzzo

Published in

Frontiers in aging neuroscience. Volume 18. Pages 1840697. Epub Jul 13, 2026.

Abstract

Early synaptic failure is widely considered a primary driver of cognitive decline in Alzheimer's disease (AD), and previous studies have suggested that dopaminergic signaling may contribute to hippocampal synaptic dysfunction. Among dopaminergic receptors, dopamine D3 receptors (D3Rs) have emerged as important modulators of synaptic plasticity and cognitive processes, but their role in AD-related synaptic impairment remains unclear. The aim of this study was to determine whether pharmacological blockade of D3Rs could restore memory deficits and hippocampal synaptic dysfunction in preclinical models of AD.
Behavioral studies, including novel object recognition (NOR), novel object location (NOL), and open-field tests, were performed to evaluate recognition memory, spatial memory, locomotor activity, and anxiety-related behavior in two mechanistically distinct mouse models of AD: triple-transgenic 3xTg-AD mice and α7 nicotinic acetylcholine receptor knockout (α7KO) mice. Electrophysiological recordings in hippocampal slices were used to assess AMPA/NMDA ratio, basal synaptic transmission, and long-term potentiation (LTP). qPCR and western blot analyses were performed to evaluate hippocampal D3R mRNA and protein expression, respectively. Pharmacological treatments included the selective D3R antagonist NGB-2904 and cariprazine, a clinically approved antipsychotic with high affinity for D3Rs.
Recognition and spatial memory deficits were rescued by NGB-2904 and cariprazine in both AD models, without affecting locomotor activity or anxiety-related behavior. No sex-dependent differences were observed in the behavioral response to treatment. Electrophysiological recordings revealed a reduced AMPA/NMDA ratio and impaired LTP in both models, while basal synaptic transmission was selectively reduced in 3xTg-AD mice. D3R-targeting compounds restored synaptic transmission and plasticity. Inhibition of PKA prevented the rescue of LTP induced by D3R blockade, suggesting the involvement of the cAMP/PKA signaling pathway. Both models displayed reduced hippocampal D3R mRNA expression and protein levels, suggesting that the residual population of D3Rs might represent a viable target.
Together, these findings demonstrate that D3R-targeting compounds rescue synaptic plasticity and memory deficits in two mechanistically distinct AD models. These results support a role for dopaminergic signaling in early synaptic dysfunction and highlights D3R modulation as a relevant pathway for further investigation in AD-related cognitive impairment.

PMID:
42516875
Bibliographic data and abstract were imported from PubMed on 28 Jul 2026.

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