Role of p21 in antidepressant-induced neurogenesis

p21 在抗抑郁药诱导的神经发生中的作用

• 批准号: 7537251
• 负责人: VERA M CHESNOKOVA
• 金额: $ 17.89万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-10 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537251
• 关键词: Antidepressive Agents; Antigens; Area; Brain; Brain region; Cell Count; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cells; Chronic; Cyclin-Dependent Kinase Inhibitor; Data; Development; Exhibits; Exploratory/Developmental Grant; Hippocampus (Brain); Human; Imipramine; Knockout Mice; Lead; Light; Major Depressive Disorder; Mammalian Cell; Mental disorders; Molecular; Monoamine Oxidase Inhibitors; Mus; Neurons; Norepinephrine; Nuclear Protein; Nuclear Proteins; Parahippocampal Gyrus; Pharmacotherapy; Phase; Play; Process; Proliferating Cell Nuclear Antigen; Proteins; Public Health; Role; Selective Serotonin Reuptake Inhibitor; Swimming; Tail Suspension; Testing; Tricyclic Antidepressive Agents; United States; Uridine; adult neurogenesis; chronic depression; dentate gyrus; depression; drug efficacy; in vivo; inhibitor/antagonist; knowledge base; nerve stem cell; neuroblast; neurogenesis; novel; oncoprotein p21; research study; reuptake

DESCRIPTION (provided by applicant): The hippocampus is a brain region where robust neurogenesis continues throughout adulthood. Hippocampal neurogenesis and hippocampal volume are reduced in humans suffering from depression, and the chronic administration of antidepressants increases neuronal proliferation in this region. Little is known about the specific mechanisms underlying the effects of antidepressants on neuronal proliferation in the hippocampus, and this is an important gap in our knowledge base. Cyclin-dependent kinase inhibitors are proteins that play a major role in restraining cellular proliferation. Our preliminary studies demonstrate that in the mouse, p21, a cyclin-dependent kinase inhibitor, is abundantly expressed in the subgranular zone of the dentate gyrus, the area where hippocampal neurogenesis occurs. In this region, p21 is co-localized with neurons, and its expression is markedly suppressed after chronic treatment with the tricyclic antidepressant imipramine. The decrease in p21 expression is associated with the increase in the number of cells expressing nuclear protein antigen NeuN, a marker for neurons, and with the induction of proliferating cell nuclear antigen PCNA, a marker of cellular proliferation. p21-null mice exhibit increased BrdU incorporation in the subgranular zone, indicating enhanced neuronal proliferation. Our findings strongly suggest that p21 plays a key role in restraining neuronal proliferation in hippocampus, and have led us to hypothesize that the action of antidepressants on neurogenesis occurs via p21 suppression. This exploratory/developmental grant will test this hypothesis and determine whether the common mechanism of different classes of antidepressants is that they increase neuronal proliferation by altering the activity of cell-cycle regulatory proteins. The results of the proposed experiments will generate new and important information on how antidepressants increase neurogenesis, and could lead to the development of novel and potentially more efficacious treatments for depression.

描述（由申请人提供）：海马是一个大脑区域，在整个成年期都会继续进行健壮的神经发生。患有抑郁症的人类海马神经发生和海马体积减少，抗抑郁药的长期给药增加了该地区的神经元增殖。关于抗抑郁药对海马神经元增殖作用的影响的特定机制知之甚少，这是我们知识库中的重要差距。依赖细胞周期蛋白的激酶抑制剂是在限制细胞增殖中起主要作用的蛋白质。我们的初步研究表明，在小鼠中，p21是一种依赖细胞周期蛋白的激酶抑制剂，在齿状回的亚颗粒下区域大量表达，这是海马神经发生的区域。在该区域中，P21与神经元共定位，其表达在慢性治疗三环抗抑郁药后抑制了明显抑制。 p21表达的降低与表达核蛋白抗原NEUN的细胞数量增加，神经元的标志物，以及诱导增殖的细胞核抗原PCNA，这是细胞增殖的标志物。 p21-null小鼠在亚晶体区域表现出BRDU掺入增加，表明神经元增殖的增强。我们的发现强烈表明，p21在限制海马神经元增殖方面起着关键作用，并导致我们假设抗抑郁药对神经发生的作用是通过p21抑制发生的。这种探索性/发展赠款将检验该假设，并确定不同类别的抗抑郁药的共同机制是否是通过改变细胞周期调节蛋白的活性来增加神经元增殖。提出的实验的结果将产生有关抗抑郁药如何增加神经发生的新的重要信息，并可能导致新颖的抑郁症治疗新颖和可能更有效的治疗方法。

项目成果

p21Cip restrains hippocampal neurogenesis and protects neuronal progenitors from apoptosis during acute systemic inflammation.

• DOI: 10.1002/hipo.22192
• 发表时间: 2013-12
• 期刊: HIPPOCAMPUS
• 影响因子: 3.5
• 作者: Zonis, Svetlana;Ljubimov, Vladimir A.;Mahgerefteh, Michael;Pechnick, Robert N.;Wawrowsky, Kolja;Chesnokova, Vera
• 通讯作者: Chesnokova, Vera

Chronic intestinal inflammation alters hippocampal neurogenesis.

• DOI: 10.1186/s12974-015-0281-0
• 发表时间: 2015-04-03
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Zonis S;Pechnick RN;Ljubimov VA;Mahgerefteh M;Wawrowsky K;Michelsen KS;Chesnokova V
• 通讯作者: Chesnokova V

Chronic peripheral inflammation, hippocampal neurogenesis, and behavior.

• DOI: 10.1016/j.bbi.2016.01.017
• 发表时间: 2016-11
• 期刊: Brain, behavior, and immunity
• 作者: Chesnokova V;Pechnick RN;Wawrowsky K
• 通讯作者: Wawrowsky K

Antidepressants stimulate hippocampal neurogenesis by inhibiting p21 expression in the subgranular zone of the hipppocampus.

• DOI: 10.1371/journal.pone.0027290
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Pechnick RN;Zonis S;Wawrowsky K;Cosgayon R;Farrokhi C;Lacayo L;Chesnokova V
• 通讯作者: Chesnokova V