Persistence of learning-induced synapses depends on neurotrophic priming of glucocorticoid receptors

Proc Natl Acad Sci U S A. 2019 Jun 25;116(26):13097-13106. doi: 10.1073/pnas.1903203116. Epub 2019 Jun 10.


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 not fully understood. Here, we show that deletion of the neurotrophin brain-derived neurotrophic factor (BDNF)-dependent GR-phosphorylation (PO4) sites 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 subunit A1 (GluA1) mediated by GR-PO4 Together, these findings indicate that regulation of GR-PO4 via activity-dependent BDNF signaling is important for the formation and maintenance of learning-dependent synapses. They also define a signaling mechanism underlying these effects.

Keywords: BDNF-Val66Met; LTP; learning and memory; stress; two-photon microscopy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Circadian Rhythm / physiology
  • Dendritic Spines / metabolism
  • Disease Models, Animal
  • Gene Knock-In Techniques
  • Glucocorticoids / metabolism
  • Homeostasis / physiology
  • Humans
  • Intravital Microscopy
  • Male
  • Memory Consolidation / physiology*
  • Mice
  • Motor Cortex / diagnostic imaging
  • Motor Cortex / physiopathology*
  • Neuronal Plasticity / physiology*
  • Phosphorylation / physiology
  • Polymorphism, Single Nucleotide
  • Receptors, AMPA / metabolism
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Signal Transduction / physiology
  • Stress, Psychological / physiopathology*
  • Synapses / metabolism


  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor
  • Glucocorticoids
  • Receptors, AMPA
  • Receptors, Glucocorticoid
  • glutamate receptor ionotropic, AMPA 1