CNIH3 is an AMPA receptor auxiliary protein that regulates glutamatergic neurotransmission by modulating AMPAR trafficking to the cell membrane and synaptic sites, while controlling their gating kinetics including activation, deactivation, and desensitization rates 1. Beyond its canonical role in synaptic transmission, CNIH3 has emerged as a significant contributor to neuropsychiatric and neurological disorders. Genome-wide association studies identified CNIH3 variants within a 1q42.11-q42.12 locus that protect against drug-resistant focal epilepsy, with higher CNIH3 expression associated with drug resistance 23. In opioid use disorder, multiple genome-wide significant CNIH3 single-nucleotide polymorphisms were identified, with the rs10799590 A allele showing robust protection against opioid dependence (odds ratio 0.64) 45. Functional studies demonstrate that Cnih3 deletion in mice impairs spatial memory, reward-cue association, and fentanyl self-administration, suggesting CNIH3 modulates learning and memory processes relevant to addiction vulnerability 6. The therapeutic potential of CNIH3-selective modulators has been demonstrated through identification of compounds with differential allosteric effects on specific AMPAR-CNIH3 complexes 1. These convergent findings establish CNIH3 as a pivotal node integrating synaptic function with cognitive and motivational processes underlying neurological and psychiatric disease susceptibility.