Connections in adult brain are highly precise, but they do not start out that way. Precision emerges during development as synaptic connections remodel, a process that requires neural activity (action potentials and synaptic transmission) and involves regression of some synapses and strengthening and stabilization of others. Neural activity also regulates neuronal genes. In an unbiased PCR-based differential screen, we made the completely unexpected discovery that MHC Class I genes are expressed in neurons and are upregulated by neural activity and visual experience (Corriveau et al, 1998; Goddard et al, 2007). To assess requirements for MHCI in the CNS, mutant mice that lack stable surface expression of all MHCI, or specific MHCI genes, were examined. Synapse regression in the developing visual system did not occur, and in adult hippocampus synaptic strengthening was greater than normal (Huh et al, 2000; Datwani et al, 2009). These observations suggest that neuronal MHCI may normally function in synaptic plasticity. Receptors could interact with neuronal MHCI and carry out these activity-dependent synaptic processes. In a systematic search, mRNA for PirB, an innate immune receptor, was found highly expressed in neurons in many regions of mouse CNS. We generated mutant mice lacking PirB function and discovered that the extent of plasticity in visual cortex is increased (Syken et al., 2006), as is synaptic strengthening in the hippocampus. Thus, PirB, like MHCI, appears to function as a “brake” on synaptic plasticity in the CNS. Moreover, the commonality of phenotypes present in these mice suggests a model (Shatz, 2009) in which PirB may bind and transduce signals from MHCI ligands in neurons. Together, results imply that this family of molecules, thought previously to function only in the immune system, may also act at neuronal synapses to limit how much- or perhaps how quickly- synapse strength changes in response to new experience. These molecules may be crucial for controlling circuit excitability and stability in developing as well as adult brain, and changes in their function may contribute to developmental disorders such as Autism and Schizophrenia.