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

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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.