TY - JOUR
T1 - Activity-dependent Nr4a2 induction modulates synaptic expression of AMPA receptors and plasticity via a Ca 2+/ CRTC1/CREB pathway
AU - Catala Solsona, Judit
AU - Lituma, Pablo J.
AU - Lutzu, Stefano
AU - Siedlecki Wullich, Dolores Josefina
AU - Fabregas Ordoñez, Cristina
AU - Miñano Molina, Alfredo Jesús
AU - Saura, Carlos A.
AU - Castillo, Pablo
AU - Rodríguez-Álvarez, José
N1 - Copyright © 2023 the authors.
Publisher Copyright:
Copyright © 2023 the authors.
PY - 2023/4/26
Y1 - 2023/4/26
N2 - 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.
AB - 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.
KW - LTD
KW - Nr4a2
KW - glutamate receptors
KW - hippocampus
KW - neuronal activity
KW - synaptic plasticity
UR - http://www.scopus.com/inward/record.url?scp=85159198559&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1341-22.2023
DO - 10.1523/JNEUROSCI.1341-22.2023
M3 - Article
C2 - 36931707
SN - 0270-6474
VL - 43
SP - 3028
EP - 3041
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 17
ER -