Gpr85, also known as SREB2, is a member of the G protein-coupled receptor family and part of the super-conserved receptor expressed in brain (SREB) sub-family along with GPR27 and GPR173. As an orphan receptor, its endogenous ligand remains unidentified. Gpr85 is highly expressed in the central nervous system, especially in the developing cerebral cortex and hippocampal formation, suggesting its importance in neural differentiation, synaptic plasticity, and cognitive functions [1,2,5].

In Gpr85 knockout mice, brain mass was increased, and learning and memory were improved [1]. SREB2/Gpr85 transgenic (over-expression) mice showed decreased new cell proliferation and new neuron survival in the dentate gyrus, along with dendritic morphology deficits of newly generated neurons. In contrast, Gpr85 knockout mice had enhanced new neuron survival and better performance in spatial pattern separation and Y-maze working memory tasks, indicating that Gpr85 negatively regulates hippocampal adult neurogenesis and related cognitive functions [4]. Also, two male patients with autism spectrum disorder (ASD) had inherited missense mutations in Gpr85. Mutated Gpr85 accumulated more, caused endoplasmic reticulum stress, and disturbed dendrite formation of hippocampal neurons, suggesting its potential role in the molecular pathogenesis of ASD [3].

In conclusion, Gpr85 is crucial for neural and synaptic plasticity, and hippocampal adult neurogenesis. Studies using Gpr85 knockout mouse models have revealed its negative regulatory role in cognitive functions. Additionally, its mutations may be associated with ASD, highlighting the importance of Gpr85 in understanding the molecular mechanisms of certain neurological disorders [1,3,4].

References:

1. Sakai, Aya, Yasui, Takeshi, Watanave, Masashi, Hirai, Hirokazu, Takeda, Shigeki. 2022. Development of novel potent ligands for GPR85, an orphan G protein-coupled receptor expressed in the brain. In Genes to cells : devoted to molecular & cellular mechanisms, 27, 345-355. doi:10.1111/gtc.12931. https://pubmed.ncbi.nlm.nih.gov/35194900/

2. Bayrak, Alp, Hanson, Julien, Laufer, Stefan, Pillaiyar, Thanigaimalai. 2022. Super-conserved receptors expressed in the brain: biology and medicinal chemistry efforts. In Future medicinal chemistry, 14, 899-913. doi:10.4155/fmc-2022-0006. https://pubmed.ncbi.nlm.nih.gov/35535715/

3. Fujita-Jimbo, Eriko, Tanabe, Yuko, Yu, Zhiling, Momoi, Mariko Y, Momoi, Takashi. 2015. The association of GPR85 with PSD-95-neuroligin complex and autism spectrum disorder: a molecular analysis. In Molecular autism, 6, 17. doi:10.1186/s13229-015-0012-5. https://pubmed.ncbi.nlm.nih.gov/25780553/

4. Chen, Qian, Kogan, Jeffrey H, Gross, Adam K, Tamura, Kouichi, Matsumoto, Mitsuyuki. 2012. SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis-dependent learning and memory. In The European journal of neuroscience, 36, 2597-608. doi:10.1111/j.1460-9568.2012.08180.x. https://pubmed.ncbi.nlm.nih.gov/22697179/

5. Hellebrand, S, Wittenberger, T, Schaller, H C, Hermans-Borgmeyer, I. . Gpr85, a novel member of the G-protein coupled receptor family, prominently expressed in the developing mouse cerebral cortex. In Brain research. Gene expression patterns, 1, 13-6. doi:. https://pubmed.ncbi.nlm.nih.gov/15018813/