Connections in adult brain are highly precise, but they do not start out that way. Precision emerges as synaptic connections remodel in a developmental process requiring neural activity. Activity also regulates neuronal gene expression. In an unbiased screen, Major Histocompatibility Class I (MHCI) genes were found to be regulated by vision, expressed in neurons, and located at synapses (Corriveau et al, 1998; Huh et al, 2000). To assess requirements for MHCI in CNS, mutant mice lacking specific MHCI genes Kb and Db, were studied. Synapse pruning in the developing visual system fails, and ocular dominance (OD) plasticity in visual cortex is greater than in WT (Lee et al, 2014; Datwani et al, 2009). In a search for receptors that interact with neuronal MHCI, PirB was foundexpressed in subsets of neurons throughout mouse CNS. In PirB KO mice, OD plasticity is enhanced (Syken et al., 2006), LTP and LTD are altered, and the pruning of dendritic spines on cortical pyramidal neurons is deficient not only during development in germline PirB KO mice (Djurisic et al, 2013), but also when a soluble decoy receptor is infused into the visual cortex of adult WT mice. Acute blockade of PirB in adult WT cortex triggers formation of new spines and functional synapses, and can also restore visual function to an amblyopic eye (Bochner et al, 2014). Thus PirB, like MHCI, appears to regulate synapse pruning and to “brake” synaptic plasticity throughout life. The commonality of phenotypes in these mutant mice suggests a model in which PirB may bind and transduce signals from MHCI ligands in neurons. Moreover, without PirB, mice do not succumb to thedevastating effects of Beta Amyloid- a main culprit for synapse and memory loss in Alzheimer’s disease (Kim et al, 2013). Together, results imply that these molecules, thought previously to function only in immunity, also act at neuronal synapses to regulate synapse pruning and plasticity in response to new experience. Changes in their function could contribute to developmental disorders such as Schizophrenia, and Alzheimer’s disease.