Activity-dependent Nr4a2 induction modulates synaptic expression of AMPA receptors and plasticity via a Ca 2+/ CRTC1/CREB pathway

Judit Catala Solsona, Pablo J. Lituma, Stefano Lutzu, Dolores Josefina Siedlecki Wullich, Cristina Fabregas Ordoñez, Alfredo Jesús Miñano Molina, Carlos A. Saura, Pablo Castillo, José Rodríguez-Álvarez*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)


Transcription factors have a pivotal role in synaptic plasticity and the associated modification of neuronal networks required for memory formation and consolidation. The nuclear receptors subfamily 4 group A (Nr4a) have emerged as possible modulators of hippocampal synaptic plasticity and cognitive functions. However, the molecular and cellular mechanisms underlying Nr4a2-mediated hippocampal synaptic plasticity are not completely known. Here, we report that neuronal activity enhances Nr4a2 expression and function in cultured mouse hippocampal neurons (both sexes) by an ionotropic glutamate receptor/Ca2+/cAMP response element-binding protein/CREB-regulated transcription factor 1 (iGluR/Ca2+/CREB/CRTC1) pathway. Nr4a2 activation mediates Brain-derived neurotrophic factor (BDNF) production and increases expression of iGluRs, thereby affecting long-term depression (LTD) at CA3-CA1 synapses in acute mouse hippocampal slices (both sexes). Altogether, our results indicate that the iGluR/Ca2+/CREB/CRTC1 pathway mediates activity-dependent expression of Nr4a2 which is involved in glutamatergic synaptic plasticity by increasing BDNF and synaptic GluA1-AMPARs. Therefore, Nr4a2 activation could be a therapeutical approach for brain disorders associated with dysregulated synaptic plasticity.
Original languageEnglish
Pages (from-to)3028-3041
Number of pages14
JournalJournal of Neuroscience
Issue number17
Publication statusPublished - 26 Apr 2023


  • LTD
  • Nr4a2
  • glutamate receptors
  • hippocampus
  • neuronal activity
  • synaptic plasticity


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