Social and contextual memory impairments induced by Amyloid-β oligomers are rescued by Sigma-1 receptor activation

Sigma-1 receptors (S1Rs) are widely expressed throughout the central nervous system and modulate neuron intracellular calcium levels, leading to changes in neurotransmitter release and neuronal activity. They also interact with various proteins and signaling pathways, playing a key role in regulating synaptic plasticity in brain areas such as the hippocampus, thereby influencing learning and memory processes. This opens a research avenue to explore S1R modulation as a potential therapeutic target in diseases involving hippocampal synaptic alterations and compromised cognitive processes, such as Alzheimer's disease (AD). Here, we hypothesize that pharmacological activation of S1R could counteract synaptic plasticity deficits and hippocampal-dependent cognitive alterations in an early-stage amyloidosis model of Alzheimer's disease, induced by intracerebroventricular (icv) administration of Aβ_1-42 oligomers (oAβ_1-42). For that purpose, we investigate ex vivo CA3-CA1 synaptic plasticity, while in vivo, we performed open field habituation and social recognition tasks to assess contextual and social memory, respectively. Our data show that pharmacological activation of S1Rs with the selective agonist PRE-084 counteract oAβ_1-42 deleterious effects on CA3-CA1 long-term synaptic plasticity (LTP), and hippocampal-dependent contextual and social memory, without alterations of spontaneous behaviors. Together, these results provide further evidence for the role of S1Rs in ameliorating hippocampal synaptic and contextual memory dysfunctions and introduce novel insight into their involvement in early amyloid-induced social memory deficits, highlighting their potential for developing comprehensive treatments for early AD. Also, the absence of adverse behavioral outcomes associated with PRE-084 treatment suggests a favorable safety profile in preclinical models, supporting its potential as a therapeutic option.