Native receptor-targeted chemogenetics (NARCH) enables reversible, cell-type-specific inhibition of endogenous G protein-coupled receptors in vivo by combining structure-guided receptor engineering with allosteric ligand design, creating receptor-inhibitor pairs in which the designer inhibitor acts as a negative allosteric modulator on wild-type receptors but as a silent allosteric ligand on engineered mutant receptors. Application of NARCH to metabotropic glutamate receptor 1 (mGlu1) reveals that mGlu1 signaling in cerebellar Purkinje cells is specifically required for consolidation rather than acquisition of motor learning, demonstrating that NARCH can dissect receptor functions with temporal and cellular precision that is inaccessible to conventional genetic or pharmacological approaches.

Understanding brain function requires tools that allow precise manipulation of receptor signaling in defined cell types within intact neural circuits. Optogenetics and conventional chemogenetic approaches primarily enable cell-type-specific control of neuronal excitability using engineered receptors or ion channels. However, direct and reversible inhibition of endogenous neurotransmitter receptors in defined cell types has remained technically inaccessible. Here, we introduce native receptor-targeted chemogenetics (NARCH), a chemogenetic strategy that integrates structure-guided receptor engineering with allosteric ligand design to achieve reversible and temporally precise inhibition of endogenous receptor signaling with cell-type specificity in vivo. By applying NARCH to metabotropic glutamate receptor 1 (mGlu1), we demonstrate that mGlu1 signaling in cerebellar Purkinje cells is required for stabilization of motor learning across training sessions in freely moving mice. NARCH thus establishes a receptor-level chemogenetic framework for causal analysis of neural circuits and behavior.