CNS, Astellas Research Institute of America LLC, Skokie, IL 60077, USA.
Eur J Neurosci. 2012 Sep;36(5):2597-608. doi: 10.1111/j.1460-9568.2012.08180.x. Epub 2012 Jun 15.
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.
SREB2/GPR85，脑表达的超保守受体（SREB）家族的一员，是脊椎动物进化中最保守的 G 蛋白偶联受体。之前的人类和小鼠遗传学研究表明，SREB2 与精神分裂症之间可能存在联系。SREB2 在海马结构中强烈表达，特别是在齿状回，该结构与精神疾病和认知功能障碍有明确的关联。然而，SREB2 在海马中的功能仍然难以捉摸。在这里，我们表明 SREB2 调节海马体的成年神经发生，从而影响认知功能。溴脱氧尿苷掺入和免疫组织化学在 SREB2 转基因（Tg，过表达）和敲除（KO，缺失突变）小鼠中进行，以定量检测成年神经发生和新生神经元树突形态。在 SREB2 突变小鼠中评估与成年神经发生改变相关的认知反应。在 SREB2 Tg 小鼠中，齿状回中新细胞增殖和新神经元存活均减少，而 SREB2 KO 小鼠齿状回中新神经元存活增强。双皮质素染色显示 SREB2 Tg 小鼠新生神经元的树突形态缺陷。在空间模式分离任务中，SREB2 Tg 小鼠表现出区分空间关系的能力下降，而 SREB2 KO 小鼠在该任务中表现出增强的能力。此外，SREB2 Tg 和 KO 小鼠在 Y 迷宫工作记忆任务中表现出相反的表型。我们的结果表明，SREB2 是成年神经发生和随后的认知功能的负调节剂。抑制 SREB2 功能可能是增强海马体成年神经发生和认知能力的一种新方法，以改善精神病患者的核心症状。
