Takebayashi, M. | bioRxiv Science

bioRxiv2023

TCF7L2: a potential key regulator of antidepressant effects on hippocampal astrocytes in depression model mice

AimClinical and preclinical studies suggest that hippocampal astrocyte dysfunction is involved in the pathophysiology of depression; however, the underlying molecular mechanisms remain unclear. Here, we attempted to identify the hippocampal astrocytic transcripts associated with antidepressant effects in a mouse model of depression. MethodsWe used a chronic corticosterone-induced mouse model of depression to assess the behavioral effects of amitriptyline, a tricyclic antidepressant. Hippocampal astrocytes were isolated using fluorescence-activated cell sorting, and RNA sequencing was performed to evaluate the transcriptional profiles associated with depressive effects and antidepressant responses. ResultsDepression model mice exhibited typical depression-like behaviors that improved after amitriptyline treatment; the depression group mice also had significantly reduced GFAP-positive astrocyte numbers in hippocampal subfields. Comprehensive transcriptome analysis of hippocampal astrocytes showed opposing responses to amitriptyline in depression group and control mice, suggesting the importance of using the depression model. Transcription factor 7 like 2 (TCF7L2) was the only upstream regulator gene altered in depression model mice and restored in amitriptyline-treated depression model mice. In fact, TCF7L2 expression was significantly decreased in the depression group. The level of TCF7L2 long non-coding RNA, which controls mRNA expression of the TCF7L2 gene, was also significantly decreased in this group and recovered after amitriptyline treatment. The Gene Ontology biological processes associated with astrocytic TCF7L2 included proliferation, differentiation, and cytokine production. ConclusionWe identified TCF7L2 as a gene associated with depression- and antidepressant-like behaviors in response to amitriptyline in hippocampal astrocytes. Our findings could provide valuable insights into the mechanism of astrocyte-mediated antidepressant effects.

neuroscience↗

bioRxiv2022

G protein-biased LPAR1 agonism promotes prototypic antidepressant effects

Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), in treating severe depression. However, the molecular mechanisms underlying the high efficacy of TCAs have not been completely understood. Herein, we found that lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, mediates the antidepressant effects of amitriptyline, a typical TCA. Amitriptyline directly bound to LPAR1 and activated downstream G protein signaling without affecting {beta}-arrestin signaling, which implied that amitriptyline could act as a G protein-biased agonist of LPAR1. This biased agonism is unique to TCAs and has not been observed in other antidepressants, such as SSRIs. Long-term infusion of mouse hippocampus with 1-oleoyl-2-O-methyl-glycerophosphothionate (OMPT), a potent G protein-biased LPAR1 agonist, induced behavior similar to that induced by antidepressants. In contrast, LPA, a non-biased agonist of LPAR1, induced anxious behavior, indicating that LPAR1 may regulate conflicting emotional behaviors because of the downstream signaling bias. Furthermore, RNA-seq analysis revealed that LPA and OMPT have opposite patterns of gene expression changes in hippocampus. Ingenuity pathway analysis indicated that chronic intrahippocampal administration of OMPT could activate LPAR1 downstream signaling (Rho and MAPK), whereas LPA suppressed LPAR1 signaling. The results reveal the unique antidepressant effects of TCAs and indicate the potential of G protein-biased agonists of LPAR1 as targets for novel antidepressants.

neuroscience↗