Modulating plasticity in adult-born neurons of the dentate gyrus

描述(申请人提供)：抑郁症是世界上导致残疾的一个主要原因，开发新的治疗方法对其治疗至关重要。最近的研究表明，对情绪有有益影响的干预措施，如运动和慢性抗抑郁药物治疗，会增加海马神经发生。此外，慢性抗抑郁药物治疗的一些行为效应需要海马神经发生。DG中的成体颗粒细胞(GC)在其发育的关键窗口表现出高度的突触可塑性，这种增强的可塑性是由含有NR2B亚单位的NMDA受体介导的。然而，成人出生的GC兴奋性的增加在行为中扮演了什么角色，目前还不清楚。这项提议将检验这样一种假设，即阻断成年出生的GCs促进DG可塑性的能力对小鼠的认知功能和抗抑郁效果有不利影响。具体地说，拟议的实验将测试成年出生的GC中NR2B亚单位的缺失对DG生理学、情境恐惧学习和抗抑郁药物的行为反应的影响。

DESCRIPTION (provided by applicant): Depression is a major cause of disability in the world, and developing novel therapeutic approaches for its treatment is of utmost importance. Recent studies have suggested that interventions that have beneficial effects on mood such as exercise and chronic antidepressant treatment increase hippocampal neurogenesis. In addition, hippocampal neurogenesis is required for some of the behavioral effects of chronic antidepressant treatment. Adult-born granule cells (GC) in the DG exhibit a heightened synaptic plasticity during a critical window of their development, an enhanced plasticity mediated by the NR2B subunit-containing NMDA receptors. Yet, it remains unknown what role this increased excitability in adult-born GCs plays in behavior. This proposal will test the hypothesis that blocking the ability for adult-born GCs to contribute to plasticity in the DG has detrimental effects on cognitive function and antidepressant efficacy in mice. Specifically, the experiments proposed will test the effect of deletion of the NR2B subunit specifically in adult-born GCs on DG physiology, contextual fear learning and behavioral response to antidepressants.