SHISA6 (also known as CKAMP52) is an AMPA receptor auxiliary protein that functions as a single transmembrane protein with a PDZ domain ligand 1. Its primary role is maintaining high-frequency synaptic transmission at hippocampal CA3-CA1 synapses by stabilizing AMPA-type glutamate receptors (AMPARs) at postsynaptic densities 1. SHISA6 binds directly to PSD-95, constraining AMPAR mobility in the plasma membrane and preventing their desensitization during sustained synaptic activity 1. This mechanism prolongs miniature excitatory postsynaptic current decay times and protects AMPARs from synaptic depression 1. Beyond synaptic function, SHISA6 has emerging roles in disease susceptibility. Genetic variants in SHISA6 associate with delayed cognitive impairment onset in two independent datasets, with the chromosome 17 association being genome-wide significant and biologically plausible given SHISA6's involvement in hippocampal post-synaptic transmission 2. In the reward circuitry, SHISA6 is selectively upregulated in D1-medium spiny neurons of the nucleus accumbens in depression-susceptible mice, where it increases neuronal excitability and promotes depression-like behaviors 3. SHISA6 variants also associate with irritable bowel syndrome susceptibility as a candidate gene identified through genome-wide meta-analysis 4.