Brain function relies on communication via neuronal synapses. Neurons build and diversify synaptic contacts using different protein combinations that define the specificity, function and plasticity potential of synapses. More than a thousand proteins have been globally identified in both pre- and postsynaptic compartments, providing substantial potential for synaptic diversity. While there is ample evidence of diverse synaptic structures, states or functional properties, the diversity of the underlying individual synaptic proteomes remains largely unexplored. Here we used 7 different Cre-driver mouse lines crossed with a floxed mouse line in which the presynaptic terminals were fluorescently labeled (SypTOM) to identify the proteomes that underlie synaptic diversity. We combined microdissection of 5 different brain regions with fluorescent-activated synaptosome sorting to isolate and analyze using quantitative mass spectrometry 18 types of synapses and their underlying synaptic proteomes. We discovered ~1800 unique synapse-enriched proteins and allocated thousands of proteins to different types of synapses. We identify commonly shared synaptic protein modules and highlight the hotspots for proteome specialization. A protein-protein correlation network classifies proteins into modules and their association with synaptic traits reveals synaptic protein communities that correlate with either neurotransmitter glutamate or GABA. Finally, we reveal specializations and commonalities of the striatal dopaminergic proteome and outline the proteome diversity of synapses formed by parvalbumin, somatostatin and vasoactive intestinal peptide-expressing cortical interneuron subtypes, highlighting proteome signatures that relate to their functional properties. This study opens the door for molecular systems biology analysis of synapses and provides a framework to integrate proteomic information for synapse subtypes of interest with cellular or circuit-level experiments.

In this study, we sought to fill an important gap in fundamental immunology research by conducting a comprehensive systems immunology analysis of daily variation in the normal human peripheral immune system. Although variation due to circadian rhythmicity was not a significant source of variation in daily B-cell levels or any CD4+ functional subset, it accounted for more than 25% of CD4+ regulatory T-cell variation and over 50% of CD8+ central memory variation. circadian rhythmicity demonstrated phase alignment within functional phenotypes. In addition, we observed that previouslydescribed mechanistic relationships can also appear in the peripheral system as phase shifting in rhythmic patterns. We identified a set of immune factors which are ubiquitously correlated with other factors and further analysis also identified a tightly-correlated "core" set whose relational structure persisted after analytically removing circadian-related variation. This core set consisted of CD8+ and its subpopulations and the NK population. In sum, the peripheral immune system can be conceptualized as a dynamic, interconnected wave-field repeating its pattern on a daily basis. Our data provide a comprehensive inventory of synchronization and correlation within this wave-field and we encourage use of our data to discover unknown mechanistic relationships which can then be tested in the laboratory.Immune variation, in both circulating cell frequency and phenotype, have been associated with multiple autoimmune diseases 1 . For example, variations in subsets of immune cells have been correlated to metabolic changes in type 1 diabetes 2,3 and found predictive of disease progression in multiple sclerosis 4 . Additionally, peripheral blood immune cell variations were demonstrated to be predictive of a post-vaccination response 5 . Over the long-term, variation within an individual appears to be relatively stable compared to variation between-individuals 6 .Shorter-term variation occurring within the course of a day (i.e., circadian) is now a well-established characteristic of human immunity in circulation 7-15 . The presence of a "master clock", entraining the organism to external light cues via the suprachiasmic nuclei of the neuroendocrine system, is thought to be a major but not exclusive driver of the circadian behavior seen in certain components of the human immune system. Circadian changes in immune cell function and abundance within the circulatory system are also thought to result from transcriptional and posttranslational feedback loops generated by a set of interplaying clock proteins and time-keeping clock genes 16 . These "peripheral clocks" and their transcription/translation are now believed to function in nearly every human cell 17 . Immune factors such as cytokines can also influence the circadian clock, providing bidirectional flow of circadian information between the neuroendocrine and immune system 18 . Mavroudis 18 hypothesized that this network of neuroendocrine-immune interactions consist of complex and integrated mole...

Neurofibromatosis type 1 (NF1) is a common monogenic neurodevelopmental disorder associated with physical and cognitive problems. The cognitive issues are thought to arise from increased release of the neurotransmitter γ-amino butyric acid (GABA). Modulating the signaling pathways causing increased GABA release in a mouse model of NF1 reverts deficits in hippocampal learning. However, clinical trials based on these approaches have so far been unsuccessful. We therefore used a combination of slice electrophysiology, in vivo two-photon calcium imaging and optical imaging of intrinsic signal in a mouse model of NF1 to investigate whether cortical development is affected in NF1, possibly causing lifelong consequences that cannot be rescued by reducing inhibition later in life. We find that in NF1 mice of both sexes, inhibition increases strongly during the development of the visual cortex and remains high. While this increase in cortical inhibition does not affect spontaneous cortical activity patterns during early cortical development, the critical period for ocular dominance plasticity is shortened in NF1 mice due to its early closure but unaltered onset. Notably, after environmental enrichment, differences in inhibitory innervation and ocular dominance plasticity between NF1 mice and wildtype litter mates disappear. These results provide the first evidence for critical period dysregulation in NF1 and suggest that treatments aimed at normalizing levels of inhibition will need to start at early stages of development. Significance: Neurofibromatosis type 1 is associated with cognitive problems for which no treatment is currently available. This study shows that in a mouse model of Neurofibromatosis type 1, cortical inhibition is increased during development and critical period regulation is disturbed. Rearing the mice in an environment that stimulates cognitive function overcomes these deficits. These results uncover critical period dysregulation as a novel mechanism in the pathogenesis of Neurofibromatosis type 1. This suggests that targeting the affected signaling pathways in Neurofibromatosis type 1 for the treatment of cognitive disabilities may have to start at a much younger age than has so far been tested in clinical trials.