bioRxiv2019
Stress can either promote or impair learning and memory. Such opposing effects depend on whether synapses persist or decay after learning. Maintenance of new synapses formed at the time of learning upon neuronal network activation depends on the stress hormone activated glucocorticoid receptor (GR) and neurotrophic factor release. Whether and how concurrent GR and neurotrophin signaling integrate to modulate synaptic plasticity and learning is unknown. Here we show that deletion of the neurotrophin BDNF-dependent GR phosphorylation sites (GR-PO4) impairs long-term memory retention and maintenance of newly formed postsynaptic dendritic spines in the mouse cortex after motor skills training. Chronic stress and the BDNF polymorphism Val66Met disrupt the BDNF-dependent GR-PO4 pathway necessary for preserving training-induced spines and previously acquired memories. Conversely, enrichment living promotes spine formation but fails to salvage training-related spines in mice lacking BDNF-dependent GR-PO4 sites, suggesting it is essential for spine consolidation and memory retention. Mechanistically, spine maturation and persistence in the motor cortex depend on synaptic mobilization of the glutamate receptor GluA1 mediated by GR-PO4. Together, these findings indicate that regulation of GR-PO4 via activity-dependent BDNF signaling is important for learning-dependent synapses formation and maintenance. They also define a new signaling mechanism underlying these effects.\n\nSIGNIFICANCE STATEMENTSignal transduction of receptors tyrosine kinase and nuclear receptors is essential for homeostasis. Phosphorylation is one of the currencies used by these receptors to support homeostatic reactions in learning and memory. Here we show that consolidation of learning-induced neuroplasticity is made possible via stress activated glucocorticoid nuclear receptor phosphorylation through the brain-derived neurotrophic tyrosine kinase pathway. Crosstalk between these pathways is specific of cell types and behavioral experience (e.g. learning, stress and enrichment living). Disruption of this response may contribute to the pathophysiology of stress-related disorders and treatment resistance.