Abstract
Enduring reorganization is accepted as a fundamental process of adult neural plasticity. The most dramatic example of this reorganization is the birth and continuously occurring incorporation of new neurons into the pre-existing network of the adult mammalian hippocampus. Based on this phenomenon we transplanted murine embryonic stem (ES)-cell derived neuronal precursors (ESNPs) into murine organotypic hippocampal slice cultures (OHC) and examined their integration. Using a precise quantitative morphological analysis combined with a detailed electrophysiology, we show a region-specific morphological integration of transplanted ESNPs into different subfields of the hippocampal tissue, resulting in pyramidal neuron-like embryonic stem cell-derived neurons (ESNs) in the Cornu Ammonis (CA1 and CA3) and granule neuron-like ESNs in the dentate gyrus (DG), respectively. Subregion specific structural maturation was accompanied by the development of dendritic spines and the generation of excitatory postsynaptic currents (EPSCs). This cell type specific development does not depend upon NMDA-receptor-dependent synaptic transmission. The presented integration approach was further used to determine the cell-autonomous function of the pan-neurotrophin receptor p75 (P75NTR), as a possible negative regulator of ESN integration. By this means we used p75NTR-deficient ESNPs to study their integration into a WT organotypic environment. We show here that p75NTR is not necessary for integration per se but plays a suppressing role in dendritic development.
Highlights
Region-specific differentiation and integration of neuronal precursors are crucial for nervous system development
Distinct Morphological Types of ES Cell-derived Neurons Initially, we examined whether pre-differentiated embryonic stem cell-derived neuronal progenitors (ESNPs) are capable of morphologically integrating into organotypic hippocampal slice cultures (OHCs)
The differentiation process was followed by transplantation of the obtained ES Cells into Neuronal Progenitors (ESNPs) into OHCs prepared from P5 wild type mice
Summary
Region-specific differentiation and integration of neuronal precursors are crucial for nervous system development. For decades candidates influencing neuronal fate and integration have been discussed External cues, such as polypeptides secreted by the surrounding tissue or adhesion molecules, and neuronal activity have been known to modulate axonal growth as well as dendritic shape and complexity [1,2,3,4]. We show here that a population of transplanted ESNPs is capable of morphologically and functionally integrating into the different subfields of the hippocampal formation in culture. P75NTR is of special interest, since it has on the one hand neurotrophins as ligands and in addition it interacts with Trk-Receptors and even has ligand-independent functions that are of relevance for ESN cell integration [14,15]. We show here that p75NTR is not necessary for integration per se but plays a growth limiting role in dendritic development
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