Complex genetic encoding of experience by NPAS4 resulting in a sophisticated reorganization of inhibition.

项目摘要 当老鼠探索丰富的环境时，海马CA 1区的锥体神经元 接受兴奋性输入和激发动作电位，以编码有关其复杂环境的信息。这 经验诱导的活性导致活性依赖性转录因子NPAS 4通过去乙酰化途径表达。 新生转录和翻译，以及预先存在的NPAS 4 mRNA的局部树突翻译。这 丰富的环境诱导的NPAS 4产生基因表达的变化，导致复杂的 重组抑制整个体细胞-树突状轴，随着CCK篮状细胞数量的增加， 突触的数目减少，放射状树突上的抑制性突触的数目减少 NPAS 4表达细胞。该提案描述了旨在确定1）遗传特性的实验 放射状靶向中间神经元类型，其在表达NPAS 4的细胞上失去突触，和2）放射状靶向中间神经元类型， 在这种复杂的重组中NPAS 4的树突状翻译的必要性。这些实验将提供 深入了解基础生物学基础的复杂调控的抑制网络和作用， 经验和活性依赖性树突翻译在此过程中发挥作用。考虑到已知的关系 抑制失调、树突翻译和各种神经系统疾病之间的关系 这项工作将有助于我们了解神经功能和功能障碍。

Project Abstract When a mouse explores an enriched environment the pyramidal neurons in the CA1 region of its hippocampus receive excitatory inputs and fire action potentials to encode information about their complex environment. This experience-induced activity results in the expression of the activity dependent transcription factor NPAS4 via de novo transcription and translation, as well as local dendritic translation of preexisting NPAS4 mRNA. This enriched environment induced NPAS4 produces changes in gene expression resulting in a sophisticated reorganization of inhibition across the somato-dendritic axis, with an increase in the number CCK Basket Cell synapses onto the somatic region and a decrease in the number of inhibitory synapses on the radiatum dendrites of NPAS4 expressing cells. This proposal describes experiments designed to determine 1) the genetic identity of the radiatum targeting interneuron type which loses synapses onto NPAS4 expressing cells, and 2) the necessity of dendritic translation of NPAS4 in this sophisticated reorganization. These experiments will provide insight into fundamental biology underlying the complex regulation of inhibitory networks and the role that experience and activity dependent dendritic translation play in this process. Given the known relationships between dysregulation of inhibition, dendritic translation, and a variety of neurological disorders with experience dependent symptomology, this work will aid our understanding of neurological function and dysfunction.