Gadd45α modulates aversive learning through post‐transcriptional regulation of memory‐related mRNA s

Abstract

Learning is essential for survival and is controlled by complex molecular mechanisms including regulation of newly synthesized mRNA s that are required to modify synaptic functions. Despite the well‐known role of RNA ‐binding proteins ( RBP s) in mRNA functionality, their detailed regulation during memory consolidation is poorly understood. This study focuses on the brain function of the RBP Gadd45α (growth arrest and DNA damage‐inducible protein 45 alpha, encoded by the Gadd45a gene). Here, we find that hippocampal memory and long‐term potentiation are strongly impaired in Gadd45a ‐deficient mice, a phenotype accompanied by reduced levels of memory‐related mRNA s. The majority of the Gadd45α ‐ regulated transcripts show unusually long 3′ untranslated regions (3′ UTR s) that are destabilized in Gadd45a ‐deficient mice via a transcription‐independent mechanism, leading to reduced levels of the corresponding proteins in synaptosomes. Moreover, Gadd45α can bind specifically to these memory‐related mRNA s. Our study reveals a new function for extended 3′ UTR s in memory consolidation and identifies Gadd45α as a novel regulator of mRNA stability.

Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons drives overconsumption of palatable food and obesity

“…Extended access to cafeteria diet in rats increased the brain electrical stimulation in the lateral hypothalamus, pointing out a deficit in the brain reward function [ 32 ]. Therefore, both our data and previous studies [ 26 , 30 , 32 ] suggest that the development of obesity is coupled with neuronal adaptations in the reward system that drive the overeating in order to alleviate the diminished reward, in which CB1 in dorsal telencephalic neurons occupies a key regulatory function. Supporting these findings, we have recently showed that the lack of CB1 in this neuronal subpopulation did not fully mitigate the development of food addiction but significantly promoted a resilient phenotype [ 33 ].…”

“…Total RNA was isolated from the olfactory cortex and brain punches. RNA isolation, reverse transcription reaction, and real-time PCR analysis were described previously [ 26 ]. In order to evaluate the rescue of CB1 gene expression after AAV-mediated gene delivery, real-time PCR analysis was carried out with Taqman mouse CB1 primers (Mm00432621_s1), and we also designed a specific pair of primers hydridizing to mouse CB1 and rat CB1 transgene (forward: TTC AAA CTG GGT GGG GTT AC; reverse: GCC TGG TGA CGA TCC TCT TA).…”

Hippocampal gene expression patterns in Sevoflurane anesthesia associated neurocognitive disorders: A bioinformatic analysis

“…Gadd45a (growth arrest and DNA damage-inducible protein 45 alpha) has been found upregulated in response to Sevoflurane along with the corresponding long noncoding RNA ( 35 ) and also activates the p53 pathway. Gadd45a is implicated in hippocampal memory and potentiation ( 36 ). Composite network analysis implicated Gadd45a, a DNA-damage-inducible gene, in modulating NF-kappa B signaling in Sevoflurane related cognitive damage.…”

Genotoxic stress response: What is the role of cytoplasmic mRNA fate?

“…[ 71 ] It stimulates DNA excision repair in vitro and promotes global DNA demethylation. [ 75–77 ] More recently, GADD45a was shown to affect the stability of mRNAs involved in memory and synaptic plasticity [ 78 ] in the hippocampus. RNA binding activity of GADD45a is essential for this regulation.…”