👤 Fernanda Daher

Understudied orphan GPCRs lack identified natural ligands, yet understanding their function is critical for therapeutic development. GPRC5B is a brain-enriched, retinoic acid (RA)-induced orphan GPCR. While RA is used to treat severe acne, chronic exposure is associated with depression, likely due to its inhibition of adult hippocampal neurogenesis. Here, we tested whether GPRC5B plays a role in the molecular and cellular mechanisms underlying RA-induced depressive-like behaviors in mice by suppressing adult hippocampal neurogenesis. We found that Gprc5b knockout (KO) mice were resilient to RA-induced behavioral effects and that RA increased GPRC5B expression in the hippocampal neurogenic subgranular zone. This correlated with RA-mediated inhibition of adult hippocampal neurogenesis, an effect absent in Gprc5b KO mice, which also exhibited a larger pool of proliferative neuronal stem cells. Collectively, these findings suggest that GPRC5B mediates RA-induced anti-neurogenic effects and depressive-like behaviors. Show less

The postsynaptic density proteins 95 (PSD95) and 93 (PSD93) belong to a family of scaffolding proteins, the membrane-associated guanylate kinases (MAGUKs), which are highly enriched in synapses and responsible for organizing the numerous protein complexes required for synaptic development and plasticity. Genetic studies have associated MAGUKs with diseases like autism and schizophrenia, but knockout mice show severe, complex defects with difficult-to-interpret behavioral abnormalities due to major motor dysfunction which is atypical for psychiatric phenotypes. Therefore, rather than studying loss-of-function mutants, we comprehensively investigated the behavioral consequences of reduced PSD95 expression, using heterozygous PSD95 knockout mice (PSD95 Show less