Major histocompatibility complex class I (MHCI) molecules modulate activity-dependent refinement and plasticity. Here, we show that MHCI also negatively regulates the density and function of cortical synapses during their initial establishment both in vitro and in vivo. MHCI molecules are expressed in cortical neurons before and during synaptogenesis. In vitro, decreasing surface MHCI (sMHCI) on neurons increases glutamatergic and GABAergic synapse density, while overexpression decreases it. In vivo, synapse density is higher throughout development in β2m−/ − mice. MHCI also negatively regulates mEPSC, but not mIPSC, amplitude and controls the balance of excitation and inhibition onto cortical neurons. sMHCI levels are modulated by activity and are necessary for activity to negatively regulate glutamatergic synapse density. Finally, acute changes in sMHCI and activity alter synapse density exclusively in early postnatal development. These results identify a novel function for immune proteins in negatively regulating the initial establishment and function of cortical connections.

The maternal and paternal genomes play different roles in mammalian brains as a result of genomic imprinting, an epigenetic regulation leading to differential expression of the parental alleles of some genes. Here we investigate genomic imprinting in the cerebellum using a newly developed Bayesian statistical model that provides unprecedented transcript-level resolution. We uncover 160 imprinted transcripts, including 41 novel and independently validated imprinted genes. Strikingly, many genes exhibit parentally biased—rather than monoallelic—expression, with different magnitudes according to age, organ, and brain region. Developmental changes in parental bias and overall gene expression are strongly correlated, suggesting combined roles in regulating gene dosage. Finally, brain-specific deletion of the paternal, but not maternal, allele of the paternally-biased Bcl-x, (Bcl2l1) results in loss of specific neuron types, supporting the functional significance of parental biases. These findings reveal the remarkable complexity of genomic imprinting, with important implications for understanding the normal and diseased brain.DOI: http://dx.doi.org/10.7554/eLife.07860.001

Immune molecules have been discovered recently to play critical roles in the development, function, and plasticity of the cerebral cortex. MHC class I (MHCI) molecules are expressed in the central nervous system and regulate activity-dependent refinement of visual projections during late postnatal development. They have also been implicated in neurodevelopmental diseases such as schizophrenia and autism. Despite the excitement generated by these unique roles for immune proteins in the brain, little is known about how these molecules regulate cortical connections. The first step toward elucidating the mechanism is to identify the spatial and temporal distribution of MHCI proteins throughout development. Using a pan-specific antibody that recognizes many MHCI variants for biochemistry and immunohistochemistry, we found that MHCI proteins are expressed in the rat visual cortex at all ages examined-during the peak of synaptogenesis, the critical period of synaptic refinement, and adulthood. Their abundance in the cortex peaked during early postnatal development, declining during periods of plasticity and adulthood. In contrast to current assumptions, pre-and postembedding immunogold electron microscopy (EM) revealed that MHCI proteins were present both pre-and postsynaptically at all ages examined. They were often found in the postsynaptic density and were closely associated with synaptic vesicles in the presynaptic terminal. These results suggest a previously undescribed model in which MHCI molecules function on both sides of the synapse to regulate connectivity in the mammalian visual cortex before, during, and after the establishment of connections.T he organization of the central nervous system (CNS) depends on the precise establishment and refinement of synaptic connections during development. These processes require a combination of neural activity and molecular mechanisms that are only just beginning to be understood (1). Improper formation and function of these synapses may lead to neurodevelopmental disorders such as schizophrenia and autism (2). A role in the developing CNS has been suggested for MHC class I (MHCI) molecules. MHCI molecules regulate activity-dependent refinement of developing visual projections, synaptic plasticity in hippocampal and cerebellar slices, and synaptic transmission in dissociated hippocampal cultures (3-7). Despite these intriguing results, there remain many unanswered questions as to how MHCI molecules affect cortical development and where and when they are expressed in the cortex.MHC is a highly polymorphic cluster of genes with some of the greatest allelic diversity in the genome. In the body, MHCI molecules mediate adaptive immunity; they present peptides derived from degraded cytosolic proteins for identification by cytotoxic lymphocytes and natural killer cells (8). Although MHCI mRNAs are expressed in the CNS, where they are regulated by activity (3, 4), the subcellular distribution of MHCI protein in neurons is more controversial (9, 10). MHCI proteins are enriched in ...

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