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Review
. 2023 Oct:71:101099.
doi: 10.1016/j.yfrne.2023.101099. Epub 2023 Aug 28.

Insufficient support for retinoic acid receptor control of synaptic plasticity through a non-genomic mechanism

Gregg Duester  1
Affiliations
Review

Insufficient support for retinoic acid receptor control of synaptic plasticity through a non-genomic mechanism

Gregg Duester. Front Neuroendocrinol. 2023 Oct.

Abstract

It is well established that retinoic acid receptors (RARs) function as nuclear receptors that control gene expression in response to binding of the ligand retinoic acid (RA). However, some studies have proposed that RAR-alpha (RARa) controls synaptic plasticity via non-genomic effects outside the nucleus, i.e. effects on mRNA translation of GluA1, a sub-unit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. In order to support this non-genomic mechanism, studies have reported RARa knockout mice or treatment with pharmacological levels of RA and RAR antagonists to propose that RARa is required to control normal synaptic plasticity. A major shortcoming of the non-genomic hypothesis is that there have been no mutational studies showing that RARa can bind the GluA1 mRNA to control GLUA1 protein levels in a non-genomic manner. Also, without a genetic study that removes the endogenous ligand RA, it is impossible to conclude that RARa and its ligand RA control synaptic plasticity through a non-genomic signaling mechanism.

Keywords: Genetic loss-of-function; GluA1; RAR-alpha; Retinoic acid signaling; Synaptic plasticity.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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