SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis‐dependent learning and memory

Abstract

SREB2/GPR85, a member of the super-conserved receptor expressed in brain (SREB) family, is the most conserved G-protein-coupled receptor in vertebrate evolution. Previous human and mouse genetic studies have indicated a possible link between SREB2 and schizophrenia. SREB2 is robustly expressed in the hippocampal formation, especially in the dentate gyrus, a structure with an established involvement in psychiatric disorders and cognition. However, the function of SREB2 in the hippocampus remains elusive. Here we show that SREB2 regulates hippocampal adult neurogenesis, which impacts on cognitive function. Bromodeoxyuridine incorporation and immunohistochemistry were conducted in SREB2 transgenic (Tg, over-expression) and knockout (KO, null-mutant) mice to quantitatively assay adult neurogenesis and newborn neuron dendritic morphology. Cognitive responses associated with adult neurogenesis alteration were evaluated in SREB2 mutant mice. In SREB2 Tg mice, both new cell proliferation and new neuron survival were decreased in the dentate gyrus, whereas an enhancement of new neuron survival occurred in SREB2 KO mouse dentate gyrus. Doublecortin staining revealed dendritic morphology deficits of newly generated neurons in SREB2 Tg mice. In a spatial pattern separation task, SREB2 Tg mice displayed a decreased ability to discriminate spatial relationships, whereas SREB2 KO mice had enhanced abilities in this task. Additionally, SREB2 Tg and KO mice had reciprocal phenotypes in a Y-maze working memory task. Our results indicate that SREB2 is a negative regulator of adult neurogenesis and consequential cognitive functions. Inhibition of SREB2 function may be a novel approach to enhance hippocampal adult neurogenesis and cognitive abilities to ameliorate core symptoms of psychiatric patients.

Effect of Schizophrenia Risk-Associated Alleles in SREB2 (GPR85) on Functional MRI Phenotypes in Healthy Volunteers

“…org/; Lewis et al, 2005). Also, the recent demonstration that SREB2 is involved in hippocampal adult neurogenesis (Chen et al, 2012) may be consistent with the notion that SREB2 may not be a risk gene specific to schizophrenia alone. Moreover, there are frequent examples of genetic variation associated with multiple psychiatric phenotypes (Millar et al, 2000).…”

“…This expression pattern is consistent with the behavioral profile of the SREB2 transgenic mice that show alterations in contextual fear conditioning, ie, the behavioral response to a stressful cage environment, which is mediated by amygdala and hippocampal formation (HF) in rodents. More recently, Chen et al (2012) showed that SREB2 affects adult neurogenesis and neurogenesis-dependent learning in a transgenic mouse model. Given these data, a reasonable prediction is that the function of the amygdalarhippocampal system would be preferentially affected in individuals carrying risk-associated alleles for rs56080411 and rs56039557 as compared with non-carriers, even in normal subjects.…”

Dysbindin-1C Is Required for the Survival of Hilar Mossy Cells and the Maturation of Adult Newborn Neurons in Dentate Gyrus

“…Similar to the protocol used previously (6,36), the apparatus for this behavioral task contained an open field (84 cm long ϫ 42 cm wide ϫ 15 cm high) and two distinct objects measuring between 2.5 and 5 cm at the base and between 5 and 15 cm tall, which were used as stimuli in these tasks. Mice between 8 and 10 weeks of age were used for the behavioral task.…”

“…The DISC1 (disrupted-inschizophrenia 1) gene is a key regulator that orchestrates the tempo of functional neuronal integration in the adult mouse brain (4). Other risk genes have also been found to be involved in the regulation of adult hippocampal neurogenesis, such as NPAS3 (neuronal PAS domain protein 3) (5) and SREB2/ GPR85 (G protein-coupled receptor 85) (6).…”

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

“…No such changes were noted when comparing single mutants with control mice. Altered exploratory behavior of ACC mice in the Y-maze suggests impaired working memory (32). To study working memory in an independent approach, we tested the mice on an eight-arm radial maze using a win-shift rule (33).…”