Genetic, structural and electrophysiological analyis of the zinc finger transcription factor Bcl11b/Ctip2 during formation and maintenance of hippocampal mossy fiber synapses

海马的主要功能包括整合和处理学习和空间记忆信息以及调节情绪行为的能力。这些功能的形态发生基础涉及新海马神经元的产生（神经发生），它们的细胞类型特异性分化和功能整合。齿状回的颗粒细胞神经元通过苔藓纤维系统正确连接到海马CA 3区的锥体细胞是成年海马功能的关键步骤。以前我们可以证明锌指转录因子Bcl 11b/Ctip 2对于苔藓纤维系统的出生后发育和成年功能是必需的（Simon等，2012; Simon等人，2016）。 在先前的应用期间，我们可以通过遗传和电生理方法证明苔藓纤维系统的结构和功能依赖于Bcl 11b/Ctip 2。目前，尚不清楚Bcl 11b/Ctip 2如何调节CA 3中苔藓纤维连接的发育和维持。该项目的目的是确定Bcl 11b/Ctip 2的调控机制，采用遗传，超微结构以及电生理策略。海马内苔藓纤维系统的损伤常见于神经精神和神经系统发育障碍。最近，我们与Christian Kubisch小组合作，确定了第一个人类BCL 11B/CTIP 2突变，并能够在小鼠海马中分析这些突变。我们期望从我们的研究，不仅阐明进一步的基本机制，转录调控过程中的发展和维护的神经元连接，但也提供了一个更好地了解重要的神经系统疾病。

Major functions of the hippocampus include its capability to integrate and process learning and spatial memory information as well as modulation of emotional behavior. The morphogenetic basis of these functions involves the generation of new hippocampal neurons (neurogenesis), their cell type specific differentiation and functional integration. The correct wiring of granule cell neurons of the dentate gyrus to pyramidal cells of the CA3 region of the cornu ammonis via the mossy fiber system is a critical step for the functionality of the adult hippocampus. Previously we could demonstrate that the zinc finger-transcription factor Bcl11b/Ctip2 is essential for the postnatal development and adult functions of the mossy fiber system (Simon et al., 2012; Simon et al., 2016). During the duration of the previous application we could demonstrate by genetic and electrophysiological methods that structure and function of the mossy fiber system depend on Bcl11b/Ctip2. Presently, it is not known how Bcl11b/Ctip2 regulates the development and maintenance of mossy fiber connectivity in CA3. The proposed project aims to determine Bcl11b/Ctip2 regulatory mechanisms by employing genetic, ultrastructural as well as electrophysiological strategies. Impairments of the intrahippocampal mossy fiber system are common with neuropsychiatric as well as developmental disorders of the nervous system. Recently, in collaboration with the group of Christian Kubisch we identified the first human BCL11B/CTIP2 mutations and were able to analyse these mutations in the murine hippocampus. We expect from our studies not only to elucidate further basic mechanisms of transcriptional regulation during development and maintenance of neuronal connectivity but also to provide a better understanding of important disorders of the nervous system.