CLPTM1 is a transmembrane protein that negatively regulates GABAergic neurotransmission by controlling GABAA receptor trafficking. Primary Function: CLPTM1 binds GABAA receptor subunits and actively traps them within the endoplasmic reticulum, preventing their forward trafficking to the plasma membrane 1. This reduces GABAergic inhibitory signaling strength. CLPTM1 operates exclusively on inhibitory GABAergic pathways without affecting glutamatergic or glycinergic transmission 1. Mechanism: CLPTM1 likely functions as a lipid scramblase facilitating GPI-anchor processing required for efficient protein trafficking from the ER 2. Knockdown of CLPTM1 increases both phasic and tonic inhibitory synaptic transmission and mimics activity-induced inhibitory synaptic scaling 1. Disease Relevance: De novo CLPTM1 missense variants (p.R454H, p.R568Q) are associated with epilepsy through reduced GABAA receptor currents and surface expression, promoting neuronal excitability 3. Additionally, CLPTM1 variants associate with episodic memory performance with gene-by-education interactions 4, and common variants influence lipid metabolism and cholesterol levels 5. Clinical Significance: These findings identify CLPTM1 as a molecular target for epilepsy therapeutics and suggest broader roles in neurodegenerative diseases and cardiometabolic traits.