scholarly journals Decrease in Calcium Concentration Triggers Neuronal Retinoic Acid Synthesis during Homeostatic Synaptic Plasticity

2011 ◽  
Vol 31 (49) ◽  
pp. 17764-17771 ◽  
Author(s):  
H.-L. Wang ◽  
Z. Zhang ◽  
M. Hintze ◽  
L. Chen
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Calcium Concentration ◽  
Acid Synthesis ◽  
Homeostatic Synaptic Plasticity

scholarly journals Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

2015 ◽  
Vol 112 (42) ◽  
pp. E5744-E5752 ◽  
Author(s):  
Kristin L. Arendt ◽  
Zhenjie Zhang ◽  
Subhashree Ganesan ◽  
Maik Hintze ◽  
Maggie M. Shin ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Critical Role ◽  
Signal Transduction Pathway ◽  
Acid Synthesis ◽  
Synaptic Activity ◽  
Homeostatic Synaptic Plasticity ◽  
Dependent Protein

Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca2+-levels to RA synthesis remains unknown. Here we identify the Ca2+-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca2+-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.

scholarly journals Synaptic Signaling by All-Trans Retinoic Acid in Homeostatic Synaptic Plasticity

Neuron ◽  
2008 ◽  
Vol 60 (2) ◽  
pp. 308-320 ◽  
Author(s):  
Jason Aoto ◽  
Christine I. Nam ◽  
Michael M. Poon ◽  
Pamela Ting ◽  
Lu Chen
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Synaptic Signaling ◽  
Homeostatic Synaptic Plasticity ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

scholarly journals FMRP Interacts with RARα in Synaptic Retinoic Acid Signaling and Homeostatic Synaptic Plasticity

2021 ◽  
Vol 22 (12) ◽  
pp. 6579
Author(s):  
Esther Park ◽  
Anthony G. Lau ◽  
Kristin L. Arendt ◽  
Lu Chen
Keyword(s):  
Mental Retardation ◽  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Fragile X Mental Retardation ◽  
Severe Intellectual Disability ◽  
Homeostatic Synaptic Plasticity

The fragile X syndrome (FXS) is an X-chromosome-linked neurodevelopmental disorder with severe intellectual disability caused by inactivation of the fragile X mental retardation 1 (FMR1) gene and subsequent loss of the fragile X mental retardation protein (FMRP). Among the various types of abnormal synaptic function and synaptic plasticity phenotypes reported in FXS animal models, defective synaptic retinoic acid (RA) signaling and subsequent defective homeostatic plasticity have emerged as a major synaptic dysfunction. However, the mechanism underlying the defective synaptic RA signaling in the absence of FMRP is unknown. Here, we show that RARα, the RA receptor critically involved in synaptic RA signaling, directly interacts with FMRP. This interaction is enhanced in the presence of RA. Blocking the interaction between FMRP and RARα with a small peptide corresponding to the critical binding site in RARα abolishes RA-induced increases in excitatory synaptic transmission, recapitulating the phenotype seen in the Fmr1 knockout mouse. Taken together, these data suggest that not only are functional FMRP and RARα necessary for RA-dependent homeostatic synaptic plasticity, but that the interaction between these two proteins is essential for proper transcription-independent RA signaling. Our results may provide further mechanistic understanding into FXS synaptic pathophysiology.

scholarly journals Synaptic retinoic acid receptor signaling mediates mTOR-dependent metaplasticity that controls hippocampal learning

2019 ◽  
Vol 116 (14) ◽  
pp. 7113-7122 ◽  
Author(s):  
Yu-Tien Hsu ◽  
Jie Li ◽  
Dick Wu ◽  
Thomas C. Südhof ◽  
Lu Chen
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Retinoic Acid Receptor ◽  
Protein Translation ◽  
Receptor Expression ◽  
Network Activity ◽  
Expression Levels ◽  
Acid Receptor ◽  
Homeostatic Synaptic Plasticity ◽  
Hebbian Plasticity

Homeostatic synaptic plasticity is a stabilizing mechanism engaged by neural circuits in response to prolonged perturbation of network activity. The non-Hebbian nature of homeostatic synaptic plasticity is thought to contribute to network stability by preventing “runaway” Hebbian plasticity at individual synapses. However, whether blocking homeostatic synaptic plasticity indeed induces runaway Hebbian plasticity in an intact neural circuit has not been explored. Furthermore, how compromised homeostatic synaptic plasticity impacts animal learning remains unclear. Here, we show in mice that the experience of an enriched environment (EE) engaged homeostatic synaptic plasticity in hippocampal circuits, thereby reducing excitatory synaptic transmission. This process required RARα, a nuclear retinoic acid receptor that doubles as a cytoplasmic retinoic acid-induced postsynaptic regulator of protein synthesis. Blocking RARα-dependent homeostatic synaptic plasticity during an EE experience by ablating RARα signaling induced runaway Hebbian plasticity, as evidenced by greatly enhanced long-term potentiation (LTP). As a consequence, RARα deletion in hippocampal circuits during an EE experience resulted in enhanced spatial learning but suppressed learning flexibility. In the absence of RARα, moreover, EE experience superactivated mammalian target of rapamycin (mTOR) signaling, causing a shift in protein translation that enhanced the expression levels of AMPA-type glutamate receptors. Treatment of mice with the mTOR inhibitor rapamycin during an EE experience not only restored normal AMPA-receptor expression levels but also reversed the increases in runaway Hebbian plasticity and learning after hippocampal RARα deletion. Thus, our findings reveal an RARα- and mTOR-dependent mechanism by which homeostatic plasticity controls Hebbian plasticity and learning.

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