GENETIC MODEL FOR THE ROLE OF NEUROGENESIS IN ANTIDEPRESSANT RESPONSE

描述(申请人提供)：重度抑郁症、双相情感障碍和精神分裂症的患者都被发现海马体体积减少，这表明海马细胞数量减少可能是多种精神疾病的常见内表型。包括抗抑郁剂、情绪稳定剂和非典型抗精神病药物在内的几类精神药物也被证明可以增加成年海马区的神经发生。成人神经发生与精神药物的行为反应之间的关系尚不清楚，但最近的证据表明，新神经元的产生可能是抗抑郁作用的关键。为了研究海马神经发生在抗抑郁反应中的作用，我们将利用一种新的成年神经发生缺陷的遗传模型：BF-1/FoxG1杂合子小鼠。BF-1/FoxG1是一种转录抑制因子，通过Smad/TGF-β途径抑制信号传导，是大脑半球正常发育所必需的。缺乏BF-1/FoxG1基因两个拷贝的小鼠在出生前不久就会死亡(E18.5)。杂合的BF-1/FoxG1小鼠存活了下来，但成年后不会产生新的神经元。因此，这些小鼠提供了几种金属疾病常见的内表型的遗传模型。为了探索增加成人神经发生对抗抑郁药物反应的关键这一假设，我们将亚慢性或慢性地用不同类别的抗抑郁药物治疗BF-1/FoxG1杂合子小鼠，包括三环抗抑郁药(阿米替林)、5羟色胺特异性再摄取抑制剂(氟西汀)和去甲肾上腺素特异性再摄取抑制剂(瑞波西汀)，并表征行为反应和对神经发生的影响(如果有的话)。这些研究的初步结果应导致旨在扩大这些发现的RO1提案。简而言之，后续研究将把这些研究扩展到其他类别的药物，包括非典型抗精神病药物，这些药物可能同样依赖于成人神经发生的临床效果。这些研究应该有助于更好地理解现有抗抑郁药物的作用机制。反过来，这应该会让人们更理性地寻找治疗抑郁症的新药，也可能治疗其他精神疾病。

DESCRIPTION (provided by applicant): Patients with major depression, bipolar disorder and schizophrenia have all been found to have decreased hippocampal volumes, suggesting that decreased hippocampal cell number may be a common endophenotype in multiple mental illnesses. Several classes of psychotropic medications including antidepressants, mood stabilizers and atypical antipsychotics have also been shown to increase neurogenesis in the adult hippocampus. The relationship between adult neurogenesis and the behavioral response to psychotropic medications remains unclear, however recent evidence suggests that generation of new neurons may be critical for antidepressant action. To investigate the role of hippocampal neurogenesis in antidepressant-response we will make use of a novel genetic model for deficits in adult neurogenesis: BF- 1/FoxG1 heterozygous mice. BF-1/FoxG1 is a transcriptional represser that inhibits signaling through the Smad/TGF-beta pathway, and is required for the normal development of the cerebral hemispheres. Mice lacking both copies of the BF-1/FoxG1 gene die shortly before birth (E18.5). Heterozygous BF-1/FoxG1 mice survive, but do not produce new neurons as adults. Thus, these mice offer a genetic model for an endophenotype common to several metal illnesses. To explore the hypothesis that increasing adult neurogenesis is critical for response to antidepressant medications we will treat BF-1/FoxG1 heterozygous mice with different classes of antidepressant medications including tricyclic antidepressants (amitriptyline), serotonin-specific reuptake inhibitors (fluoxetine) and norepinephrine-specific reuptake inhibitors (reboxetine), either subchronically or chronically and characterize both the behavioral response and the effects (if any) on neurogenesis. Preliminary results from these studies should lead to an RO1 proposal aimed at extending these findings. Briefly, follow up studies will extend these studies to other classes of medications including atypical antipsychotics, which may similarly be dependent on adult neurogenesis for their clinical effects. These studies should lead to a better understanding of the mechanism of action of existing antidepressant medications. This, in turn, should allow for a more rational search for new medications for the treatment of depression, and potentially other mental illnesses as well.