Regulation of CNS synapses by neuronal MHC class I

Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2007; 104(16):6828-33. DOI: 10.1073/pnas.0702023104
Source: PubMed


Until recently, neurons in the healthy brain were considered immune-privileged because they did not appear to express MHC class I (MHCI). However, MHCI mRNA was found to be regulated by neural activity in the developing visual system and has been detected in other regions of the uninjured brain. Here we show that MHCI regulates aspects of synaptic function in response to activity. MHCI protein is colocalized postsynaptically with PSD-95 in dendrites of hippocampal neurons. In vitro, whole-cell recordings of hippocampal neurons from beta2m/TAP1 knockout (KO) mice, which have reduced MHCI surface levels, indicate a 40% increase in mini-EPSC (mEPSC) frequency. mEPSC frequency is also increased 100% in layer 4 cortical neurons. Similarly, in KO hippocampal cultures, there is a modest increase in the size of presynaptic boutons relative to WT, whereas postsynaptic parameters (PSD-95 puncta size and mEPSC amplitude) are normal. In EM of intact hippocampus, KO synapses show a corresponding increase in vesicles number. Finally, KO neurons in vitro fail to respond normally to TTX treatment by scaling up synaptic parameters. Together, these results suggest that postsynaptically localized MHCl acts in homeostatic regulation of synaptic function and morphology during development and in response to activity blockade. The results also imply that MHCI acts retrogradely across the synapse to translate activity into lasting change in structure.

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    • "Several lines of evidence support OX-18's ability to bind to MHCI in the mouse nervous system. First, genetically deleting the MHCI light chain, β2m, reduces the amount of MHCI that reaches the cell surface (Dorfman et al., 1997;Zijlstra et al., 1989), and cell surface OX-18 immunofluorescence is greatly attenuated in both β2m −/− (Needleman et al., 2010) and β2m −/− TAP −/− (Goddard et al., 2007) neurons in vitro. Second, OX-18 recognizes proteins of the expected molecular weight in Western blots of adult mouse brain (Corriveau et al., 1998;Dixon-Salazar et al., 2014;Huh et al., 2000) and similar labeling is seen in rat brain using a rabbit polyclonal antibody that recognizes a distinct epitope of MHCI (Needleman et al., 2010). "
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    ABSTRACT: The major histocompatibility complex class I (MHCI) is a large gene family, with over 30 members in mouse. Some MHCIs are well-known for their critical roles in the immune response. Studies in mice which lack stable cell-surface expression of many MHCI proteins suggest that one or more MHCIs also play unexpected, essential roles in the establishment, function, and modification of neuronal synapses in the central nervous system (CNS). However, there is little information about which genes mediate MHCI's effects in neurons. In this study, RT-PCR was used to simultaneously assess transcription of many MHCI genes in regions of the central and peripheral nervous system where MHCI has a known or suspected role. In the hippocampus, a part of the CNS where MHCI regulates synapse density, synaptic transmission, and plasticity, we found that more than a dozen MHCI genes are transcribed. Single-cell RT-PCR revealed that individual hippocampal neurons can express more than one MHCI gene, and that the MHCI gene expression profile of CA1 pyramidal neurons differs significantly from that of CA3 pyramidal neurons or granule cells of the dentate gyrus. MHCI gene expression was also assessed at the neuromuscular junction (NMJ), a part of the peripheral nervous system (PNS) where MHCI plays a role in neuronal regeneration, and could potentially influence developmental synapse elimination. Four MHCI genes are expressed at the NMJ at an age when synapse elimination is occurring in three different muscles. Several MHCI mRNA splice variants were detected in hippocampus, but not at the NMJ. Together, these results establish the first profile of MHCI gene expression at the developing NMJ, and demonstrate that MHCI gene expression is under tight spatial and temporal regulation in the nervous system. They also identify more than a dozen MHCIs that could play important roles in synaptic transmission and plasticity in the central and peripheral nervous systems.
    Full-text · Article · Jan 2016 · Molecular and Cellular Neuroscience
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    • "Apart from regulating immunity, the MHC genes may have a role in reproduction and social behavior, such as pregnancy maintenance, mate selection, and kin recognition[15]. The MHC genomic region also appears to influence drug adverse reactions[16,17], CNS development and plasticity[18– 22], neurological cell interactions[23,24], synaptic function and behavior[25,26], cerebral hemispheric specialization[27], and neurological and psychiatric disorders2829303132. Hence, the MHC is one of the most biomedically important genomic regions that warrant special attention for genetic investigation. "
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    ABSTRACT: The major histocompatibility complex (MHC) is a highly polymorphic genomic region that encodes the transplantation and immune regulatory molecules. It receives special attention for genetic investigation because of its important role in the regulation of innate and adaptive immune responses and its strong association with numerous infectious and/or autoimmune diseases. Recently, genotyping of the polymorphisms of MHC genes using targeted next-generation sequencing (NGS) technologies was developed for humans and some nonhuman species. Most species have numerous highly homologous MHC loci so the NGS technologies are likely to replace traditional genotyping methods in the near future for the investigation of human and animal MHC genes in evolutionary biology, ecology, population genetics, and disease and transplantation studies. In this chapter, we provide a short review of the use of targeted NGS for MHC genotyping in humans and nonhuman species, particularly for the class I and class II regions of the Crab-eating Macaque MHC (Mafa).
    Full-text · Chapter · Jan 2016
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    • "Recently, Paolicelli and collaborators showed that CX 3 CR1 knock-out (KO) mice have fewer microglia in postnatal hippocampus compared to wild type mice at the same age. These findings are consistent with previous data suggesting that immune molecules, such as class I molecules of histocompatibility major complex (MHC1), complement cascade molecules and neuronal pentraxins, contribute to synaptic elimination or strengthening during development (Boulanger, 2009; Corriveau et al., 1998; Datwani et al., 2009; Goddard et al., 2007; Huh et al., 2000; Schafer et al., 2012; Stevens et al., 2007) (Fig. 1). For instance, complement proteins C1q and C3, have emerged as critical mediators of synaptic refinement and plasticity (Schafer et al., 2012; Stephan et al., 2012; Stevens et al., 2007). "
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    ABSTRACT: The central nervous system (CNS) has previously been regarded as an immune-privileged site with the absence of immune cell responses but this dogma was not entirely true. Microglia are the brain innate immune cells and recent findings indicate that they participate both in CNS disease and infection as well as facilitate normal CNS function. Microglia are highly plastic and play integral roles in sculpting the structure of the CNS, refining neuronal circuitry and connectivity, and contribute actively to neuronal plasticity in the healthy brain. Interestingly, psychological stress can perturb the function of microglia in association with an impaired neuronal plasticity and the development of emotional behavior alterations. As a result it seemed important to describe in this review some findings indicating that the stress-induced microglia dysfunction may underlie neuroplasticity deficits associated to many mood disorders. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jan 2015 · Neuropharmacology
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