Connections in the adult visual system are highly precise, but they do not start out that way. Precision emerges during critical periods of development as synaptic connections remodel, a process requiring neural activity and involving regression of some synapses and strengthening and stabilization of others. We discovered, unexpectedly, that MHC Class I genes and an innate immune receptor, PirB, are involved in this process. Thus, MHCI ligands signaling via PirB receptor may function to "brake" activity- dependent synaptic plasticity. Together, results imply that these molecules, thought previously to function only in the immune system, also act at neuronal synapses to limit how much- or perhaps how rapidly- synapse strength changes in response to new experience. Changes in the function of these molecules may also contribute to developmental disorders such as autism and schizophrenia. (#23415)