Estibaliz Ampuero, Nur Jury, Steffen Härtel, María Paz Marzolo & Brigitte van Zundert
Journal of Cellular Physiology, Sep 21. doi: 10.1002/jcp.25605. [Epub ahead of print]

Reelin is an extracellular glycoprotein secreted in the embryonic and adult brain with roles in neuronal migration and structural and functional plasticity. Extensive evidence shows that reelin via activation of its receptors ApoER2 and VLDLR promotes dendrite and spine formation during early development. Its has been suggested that reelin signaling is required to maintain a stable architecture in mature neurons, however, 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, in a splice variant dependent manner, interacts with PSD95, we tested if reelin signaling interference in adult neurons leads to reactivation of the dendritic architecture. Unlike findings in developing cultures, here we report for the first time that reelin signaling interference robustly increased dendritogenesis and reduced spine density in mature hippocampal neurons in vitro and in vivo. Particularly, the finding that expression of an ApoER2 form (ApoER2-tailless), unable to interact with PSD95 and hence cannot transduce reelin signaling, resulted in robust dendritogenesis in mature hippococampal neurons in vitro indicate that reelin/ApoER2/PSD95 signaling is important for neuronal structure maintenance. Mechanistically, our immunofluorescent data indicate that reelin signaling blockage reduced synaptic PSD95 levels, and consequently led to synaptic re-insertion of NR2B-NMDARs. Our findings underscore the importance of reelin in maintaining adult network stability, and reveal a new mode to reactivate structural plasticity in neurological disorders where spine density and dendrite arbor complexity are limited, such as in depression, Alzheimer’s disease and stroke.