Cornichon Homolog-3 (Cnih3) deletion impairs spatial memory, operant learning, and fentanyl self-administration behavior.

Opioid misuse remains rampant as new synthetic opioids reach the market. Large-scale genetic tools like the GWAS identify previously unrecognized targets and biomarkers in opioid misuse with the hopes of combating the opioid epidemic. One such target is the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) auxiliary protein Cornichon Homolog-3 (human analog: CNIH3, mouse analog: Cnih3), which determines AMPAR subunit composition and kinetics: important factors in opioid use. Though CNIH3 was identified as a gene of interest in OUD, its role in opioid use and related behavior has not been studied. Using mice with Cnih3 deletion, we characterize the role of Cnih3 in a battery of behaviors that encompass well-being, affect, spatial and social memory, operant learning, reversal learning, and opioid use itself. We find that Cnih3 deletion moderately impairs spatial memory in the novel object recognition task, as well as operant learning in a sucrose self-administration paradigm. Cnih3 deletion also delays acquisition of fentanyl IVSA in females and blunts fentanyl intake during IVSA in both sexes. We use principal component analysis to pinpoint the dimensions in which Cnih3 deletion impacts the behaviors tested in an unbiased manner. These findings, combined with initial GWAS findings, identify Cnih3 as a behaviorally relevant protein in opioid-related plasticity.