Activity-Dependent Nr4a2 Induction Modulates Synaptic Expression of AMPA Receptors and Plasticity via a Ca^2+/CRTC1/CREB Pathway

Abstract

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.SIGNIFICANT STATEMENT:A major factor that regulates fast excitatory synaptic transmission and plasticity is the modulation of synaptic AMPA receptors. However, despite decades of research, the underlying mechanisms of this modulation remain poorly understood. Our study identified a molecular pathway that links neuronal activity with AMPA receptor modulation and hippocampal synaptic plasticity through the activation of Nr4a2, a member of the nuclear receptor subfamily 4. Since several compounds have been described to activate Nr4a2, our study not only provides mechanistic insights into the molecular pathways related to hippocampal synaptic plasticity and learning, but also identifies Nr4a2 as a potential therapeutic target for pathological conditions associated with dysregulation of glutamatergic synaptic function.

Nr4a2 blocks oAβ-mediated synaptic plasticity dysfunction and ameliorates spatial memory deficits in the APPSw,Indmouse

“…It is now widely accepted that oAβ are one of the initial mediators leading to early synaptic dysfunction in AD (Forner et al, 2017). Since we have previously reported that Nr4a2 has a key role in hippocampal synaptic plasticity (Català-Solsona et al, 2023), we wanted to address the eventual involvement of Nr4a2 in the synaptic failure occurring at early AD stages. For that purpose, we firs addressed whether oAβ could alter Nr4a2 levels in hippocampal neurons (Fig.…”

“…A mechanism involved in this effect is the oAβ-mediated decrease of surface expression of AMPARs (Hsieh et al, 2006; Minano-Molina et al, 2011). Since, we have recently reported that Nr4a2 activation increases postsynaptic AMPARs and effectively blocks LTD (Català-Solsona et al, 2023), we addressed whether Nr4a2 activation was able to rescue the oAβ-mediated deficits in hippocampal synaptic plasticity. We used the Nr4a2 activator amodiaquine (AQ) to test the effect of Nr4a2 activation on cLTD in primary cultures of hippocampal neurons (Fig.…”

“…Primary hippocampal neurons were obtained from C57BI-6J/RccHsd mice pups (postnatal days 0-2). Neurons were mechanically and enzymatically dissociated with papain (Sigma) and plated (66,000 neurons/cm 2 ) in Neurobasal-A medium supplemented with 2% B27 (Fisher Scientific) as previously described (Català-Solsona et al, 2023). Experiments were performed when hippocampal neurons were mature (18-21 DIV).…”

“…The mechanisms involved in Nr4a2-mediated hippocampal synaptic plasticityare poorly understood. Recently, we reported that neuronal activity triggers an ionotropic glutamate receptor/Ca 2+ /CREB-CRTC1 pathway that mediates Nr4a2 activation which modulates hippocampal synaptic plasticity by increasing BDNF and synaptic AMPARs (Català-Solsona et al, 2023).…”

Differential Chromatin Architecture and Risk Variants in Deep Layer Excitatory Neurons and Grey Matter Microglia Contribute to Major Depressive Disorder

“…Chemogenetic silencing of these neurons attenuates stress-induced anxiety- and depression-like behaviors in rodents 61 . Moreover, activity-dependent induction of NR4A2 can modulate AMPA-receptor mediated synaptic plasticity 82 whose alterations are strongly associated with depression 83 .…”