Language
English
Publication Date
7-1-2026
Journal
eNeuro
DOI
10.1523/ENEURO.0430-25.2026
PMID
42469032
PMCID
PMC13423511
PubMedCentral® Posted Date
7-28-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Chronic ethanol (EtOH) exposure and withdrawal are linked to worsened memory and cognitive outcomes. One target of EtOH is the glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Both EtOH exposure and withdrawal influences AMPAR expression, function, and broad glutamate signaling. Previous work suggests that EtOH regulation of AMPARs drives behaviors related to dependence and memory phenotypes. However, due to the complexity of the mammalian brain, it is difficult to unravel the precise mechanism by which EtOH regulates AMPARs in mammals to modify specific memory behaviors. In Caenorhabditis elegans, GLR-1, an AMPAR ortholog, has tightly defined expression in relatively few neurons, conserved regulatory mechanisms, and is linked to molecularly conserved associative behaviors including those disrupted by EtOH. Using an established paradigm that exposes worms to chronic EtOH and cessation (“withdrawal”), we examined the relationship between EtOH withdrawal, associative memory, and GLR-1/AMPAR regulation. We found that withdrawal from chronic EtOH disrupts intermediate-term associative memory (ITM) in wild-type worms, phenocopying loss of GLR-1 function. ITM is rescued by EtOH reintroduction, suggesting a “withdrawal-like” phenotype. Losing GLR-1 occludes the ITM deficit and EtOH-ceased wild-type phenocopy glr-1 loss-of-function in other glr-1-regulated behaviors. Withdrawal broadly alters GLR-1 expression, downregulates glr-1, and increases CREB-mediated transcriptional activity in neurons in a JNK kinase-dependent manner. Loss of JNK and downstream transcription factor CREB prevent these EtOH withdrawal phenotypes. Overall, we have identified a transcriptional regulatory cascade driven by JNK–CREB signaling that may help neurons adapt glr-1 signaling in response to continuous EtOH exposure and abrupt withdrawal, leading to behavior deficits.
Keywords
Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Ethanol, Substance Withdrawal Syndrome, Receptors, AMPA, Central Nervous System Depressants, Association Learning, Animals, Genetically Modified, Signal Transduction, Memory, Cyclic AMP Response Element-Binding Protein, AMPA receptors, C. elegans, CREB, ethanol, kinase, learning and memory
Published Open-Access
yes
Recommended Citation
Katie Brandel-Ankrapp and Rachel N Arey, "Altered glr-1 Expression after EtOH Withdrawal Is Linked to Associative Behavior Deficits in C. elegans" (2026). Faculty, Staff and Students Publications. 7972.
https://digitalcommons.library.tmc.edu/baylor_docs/7972