Blockade of dopamine D3 receptors improves hippocampal synaptic function and rescues age-related cognitive phenotype.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101130839 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-9726 (Electronic) Linking ISSN: 14749718 NLM ISO Abbreviation: Aging Cell Subsets: MEDLINE

Publication: Oxford, UK : Wiley-Blackwell
Original Publication: Oxford, UK : Blackwell Pub., c2002-

Receptors, Dopamine D3*/metabolism ; Receptors, Dopamine D3*/genetics ; Hippocampus*/metabolism ; Cognition*/physiology; Animals ; Mice ; Mice, Knockout ; Synapses/metabolism ; Aging/physiology ; Aging/metabolism ; Male ; Phenotype ; Mice, Inbred C57BL ; Long-Term Potentiation ; Synaptic Transmission

Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro-cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long-term potentiation (LTP1) into the stronger long-lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long-term memory. D3R effects were mainly mediated by post-synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR-mediated currents, mEPSC amplitude, and the expression of the post-synaptic proteins PSD-95, phospho(p)GluA1 and p-CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post-synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post-synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post-synaptic protein expression, and PSD length. Notably, aged D3-KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age-related hippocampal cognitive decline.
(© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

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PRIN 2020AMLXHH Italian Ministry of University and Research; PRIN 2022BZWEK Italian Ministry of University and Research; PRIN 2022YEPFB7 Italian Ministry of University and Research; University of Catania Progetto Piaceri; Italian Ministry of Health Ricerca Corrente Fondazione IRCCS Policlinico Univ Ricerca Corrente IRCCS Oasi Research Institute

Keywords: aging; dopamine D3 receptors; hippocampus; memory; synaptic plasticity

0 (Receptors, Dopamine D3)

Date Created: 20240905 Date Completed: 20241114 Latest Revision: 20241116

20241116

PMC11561665

10.1111/acel.14291

39236310