SHISA9 is an auxiliary subunit of AMPA-type glutamate receptors that regulates short-term neuronal synaptic plasticity, primarily in the hippocampus and dentate gyrus 1. As a type-I transmembrane protein, SHISA9 associates with AMPA receptors in synaptic spines and modulates their physiological properties, particularly promoting AMPA receptor desensitization at excitatory synapses 2. The protein's C-terminal PDZ domain interacts with postsynaptic density scaffolding proteins, and disruption of these interactions alters glutamatergic synaptic currents and network activity 1. SHISA9 belongs to the CKAMP family of AMPA receptor-modulating proteins that influence receptor trafficking, subcellular localization, and function 2. SHISA9 is classified as a single-transmembrane adaptor protein with a cysteine-rich domain, suggesting broader regulatory roles in membrane protein trafficking 3. Clinically, SHISA9 has emerged as a disease-relevant gene across multiple psychiatric and other conditions. Genome-wide association studies identified SHISA9 as a schizophrenia risk locus 4, and transcriptomic analysis revealed marked downregulation of SHISA9 in paraventricular thalamic nucleus neurons from bipolar disorder patients 5. Additionally, SHISA9 variants are associated with periodontitis susceptibility 6 and appear in hepatocellular carcinoma prognostic signatures 7.