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.

Global epigenetic analysis of BDNF Val66Met mice hippocampus reveals changes in dendrite and spine remodeling genes

“…However, deficits in Reln expression have been also reported in animal models of depression . Interestingly, a recent study reported that blocking the Reln signaling pathway increases dendritic growth and branching in adult neurons, which is in contrast with previous studies showing that deficiency in Reln signaling impairs dendritic development (Ampuero et al, 2017). Our results showing increased AcH3 at Genes indicated in bold were identified by GREAT.…”

“…However, deficits in Reln expression have been also reported in animal models of depression (Caruncho et al, ). Interestingly, a recent study reported that blocking the Reln signaling pathway increases dendritic growth and branching in adult neurons, which is in contrast with previous studies showing that deficiency in Reln signaling impairs dendritic development (Ampuero et al, ). Our results showing increased AcH3 at the Reln promoter, and the corresponding augmented expression of Reln mRNA in BDNF Met/Met mice, suggest that elevated Reln levels reduce the dendritic growth in adult hippocampal neurons, as shown by Ampuero and colleagues (Ampuero et al, ).…”

“…Interestingly, a recent study reported that blocking the Reln signaling pathway increases dendritic growth and branching in adult neurons, which is in contrast with previous studies showing that deficiency in Reln signaling impairs dendritic development (Ampuero et al, ). Our results showing increased AcH3 at the Reln promoter, and the corresponding augmented expression of Reln mRNA in BDNF Met/Met mice, suggest that elevated Reln levels reduce the dendritic growth in adult hippocampal neurons, as shown by Ampuero and colleagues (Ampuero et al, ). Alternatively, increased Reln levels could be an adaptive change needed to balance the reduced dendritic arborization observed in these mice (Chen et al, ).…”

“…the Reln promoter, and the corresponding augmented expression of Reln mRNA in BDNF Met/Met mice, suggest that elevated Reln levels reduce the dendritic growth in adult hippocampal neurons, as shown by Ampuero and colleagues (Ampuero et al, 2017). Alternatively, increased Reln levels could be an adaptive change needed to balance the reduced dendritic arborization observed in these mice (Chen et al, 2006).…”

NMDA receptor subunit composition controls dendritogenesis of hippocampal neurons through CAMKII, CREB‐P, and H3K27ac

“…Despite that dendritic branches stabilize during maturation (Chow et al, ; Koleske, ), remarkably, dendritogenesis in mature neurons can be robustly reactivated when NR2B‐NMDARs are reinserted into the synapse by reducing the synaptic levels of PSD95, a critical scaffolding protein that anchors NR2A‐NMDARs at the PSD (Ampuero, Jury, Härtel, Marzolo, & van Zundert, ; Bustos et al, ; Charych et al, ; Henriquez et al, ). The precise molecular basis for how NR2B‐NMDARs, and not NR2A‐NMDARs, induce dendritic outgrowth is currently unknown.…”