title: Interfering of the Reelin/ApoER2/PSD95 Signaling Axis Reactivates Dendritogenesis of Mature Hippocampal Neurons.
abstract: Reelin, an extracellular glycoprotein secreted in embryonic and adult brain, participates in neuronal migration and neuronal plasticity. Extensive evidence shows that reelin via activation of the ApoER2 and VLDLR receptors promotes dendrite and spine formation during early development. Further evidence suggests that reelin signaling is needed to maintain a stable architecture in mature neurons, but, direct evidence is lacking. During activity-dependent maturation of the neuronal circuitry, the synaptic protein PSD95 is inserted into the postsynaptic membrane to induce structural refinement and stability of spines and dendrites. Given that ApoER2 interacts with PSD95, we tested if reelin signaling interference in adult neurons reactivates the dendritic architecture. Unlike findings in developing cultures, the presently obtained in vitro and in vivo data show, for the first time, that reelin signaling interference robustly increase dendritogenesis and reduce spine density in mature hippocampal neurons. In particular, the expression of a mutant ApoER2 form (ApoER2-tailless), which is unable to interact with PSD95 and hence cannot transduce reelin signaling, resulted in robust dendritogenesis in mature hippocampal neurons in vitro. These results indicate that reelin/ApoER2/PSD95 signaling is important for neuronal structure maintenance in mature neurons. Mechanistically, obtained immunofluorescent data indicate that reelin signaling impairment reduced synaptic PSD95 levels, consequently leading to synaptic re-insertion of NR2B-NMDARs. Our findings underscore the importance of reelin in maintaining adult network stability and reveal a new mode for reactivating dendritogenesis in neurological disorders where dendritic arbor complexity is limited, such as in depression, Alzheimer's disease, and stroke. J. Cell. Physiol. 232: 1187-1199, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Ampuero
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Nur
authors.initials: N
authors.lastname: Jury
authors.affiliation: SCIAN-Lab, CIMT, Bomedical Neuroscience Institute (BNI), ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Steffen
authors.initials: S
authors.lastname: Härtel
authors.affiliation: Laboratorio de Tráfico Intracelular y Señalización, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica, Santiago, Chile.
authors.forename: María-Paz
authors.initials: MP
authors.lastname: Marzolo
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Brigitte
authors.initials: B
authors.lastname: van Zundert
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002454:Cell Differentiation; D003712:Dendrites / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005799:Genes, Dominant; D005982:Glutathione Transferase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D055495:Neurogenesis; D009473:Neuronal Plasticity; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D016326:Extracellular Matrix Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; C098773:low density lipoprotein receptor-related protein 8; C103332:GST-RAP protein, recombinant; D005982:Glutathione Transferase; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases