Chronic central modulation of LPA/LPA receptors-signaling pathway in the mouse brain regulates cognition, emotion, and hippocampal neurogenesis

Several studies have demonstrated that lysophosphatidic acid (LPA) acts through its LPA receptors in multiple biological and behavioral processes, including adult hippocampal neurogenesis, hippocampal-dependent mem-ory, and emotional regulation. However, analyses of the effects have typically involved acute treatments, and there is no information available regarding the effect of the chronic pharmacological modulation of the LPA/LPA receptors-signaling pathway. Thus, we analyzed the effect of the chronic (21 days) and continuous intra-cerebroventricular (ICV) infusion of C18:1 LPA and the LPA(1-3) receptor antagonist Ki16425 in behavior and adult hippocampal neurogenesis. Twenty-one days after continuous ICV infusions, mouse behaviors in the open field test, Y-maze test and forced swimming test were assessed. In addition, the hippocampus was examined for c-Fos expression and alpha-CaMKII and phospho-alpha-CaMKII levels. The current study demonstrates that chronic C18:1 LPA produced antidepressant effects, improved spatial working memory, and enhanced adult hippocampal neurogenesis. In contrast, chronic LPA(1-3) receptor antago-nism disrupted exploratory activity and spatial working memory, induced anxiety and depression-like behaviors and produced an impairment of hippocampal neurogenesis. While these effects were accompanied by an increase in neuronal activation in the DG of C18:1 LPA-treated mice, Ki16425-treated mice showed reduced neuronal activation in CA3 and CA1 hippocampal subfields. Treatment with the antagonist also induced an imbalance in the expression of basal/activated alpha-CaMKII protein forms. These outcomes indicate that the chronic central modulation of the LPA receptors-signaling pathway in the brain regulates cognition and emotion, likely comprising hippocampal-dependent mechanisms. The use of pharmacological modulation of this pathway in the brain may potentially be targeted for the treatment of several neuropsychiatric conditions.

Automated summary

The chronic modulation of the LPA/LPA receptors-signaling pathway in the brain plays a crucial role in regulating cognition and emotion, particularly through hippocampal-dependent mechanisms. Chronic C18:1 LPA infusion leads to antidepressant effects, improved memory, and enhanced hippocampal neurogenesis, while LPA(1-3) receptor antagonist disrupts memory and induces anxiety and depression-like behaviors.