Gpr85, a member of the G protein-coupled receptor family, belongs to the super-conserved receptor expressed in brain (SREB) sub-family along with GPR27 and GPR173. As an orphan receptor, its endogenous ligand remains unidentified. It is prominently expressed in the central nervous system, playing potential roles in regulating neural and synaptic plasticity, and modulating behaviors such as learning and memory [1,2]. It may be involved in pathways related to brain-associated functions, and its study using genetic models like knockout mice is valuable for understanding its functions [1,3].

In Gpr85 knockout mice, brain mass is reported to be increased, and learning and memory are improved [1]. SREB2/Gpr85 transgenic (over-expression) mice show decreased new cell proliferation and new neuron survival in the dentate gyrus, along with dendritic morphology deficits of newly generated neurons. These mice display reduced abilities in spatial pattern separation and Y-maze working memory tasks. In contrast, Gpr85 knockout mice have enhanced new neuron survival, as well as improved abilities in the spatial pattern separation task and opposite phenotypes in the Y-maze working memory task, indicating that Gpr85 negatively regulates hippocampal adult neurogenesis and related cognitive functions [3]. Two male patients with autism spectrum disorder (ASD) from independent Japanese families had inherited missense mutations in Gpr85. Mutated Gpr85 accumulated more preferentially, causing endoplasmic reticulum stress and disturbing dendrite formation of hippocampal neurons, suggesting Gpr85's potential involvement in the molecular pathogenesis of ASD [2].

In conclusion, Gpr85 is a key regulator of hippocampal adult neurogenesis and related cognitive functions. Its knockout in mice reveals its negative regulatory role in these processes. The identification of mutations in Gpr85 in ASD patients also implies its significance in the molecular pathogenesis of ASD. These model-based studies provide insights into the biological functions of Gpr85 and its potential implications in neurological disorders.