Functional requirement for class I MHC in CNS development and plasticity

Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
Science (Impact Factor: 33.61). 01/2001; 290(5499):2155-9.
Source: PubMed


Class I major histocompatibility complex (class I MHC) molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. Here, we show that in mice genetically deficient for cell surface class I MHC or for a class I MHC receptor component, CD3zeta, refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) is enhanced, and long-term depression (LTD) is absent. Specific class I MHC messenger RNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrate an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system (CNS).

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Available from: Lisa M Boulanger, Oct 03, 2015
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    • "NMDA receptors require the binding of glycine and glutamate in combination with the release of voltage-dependent magnesium blockage. In addition to its role during CNS development, neuronal activity via NMDA receptors also imparts neuronal plasticity, memory formation, and learning that require associated transcriptional changes to mediate physiological responses (Huh et al. 2000; Kandel 2001; Nestler and Landsman 2001; Zhang et al. 2007; Chen et al. 2014). Evidence suggests that NMDA receptor activation leads to strengthening of synapses through long-term potentiation (LTP) and to the weakening of synapses through long-term depression (LTD) (Sanchez-Perez et al. 2005; Massey and Bashir 2007; Zhang et al. 2007; Chen et al. 2014; Connor and Wang 2015). "
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    ABSTRACT: Gene regulation in mammals involves a complex interplay between promoters and distal regulatory elements that function in concert to drive precise spatio-temporal gene expression programs. However, the dynamics of distal gene regulatory landscape and its function in the transcriptional reprogramming that underlies neurogenesis and neuronal activity remain largely unknown. Here, we performed a combinatorial analysis of genome-wide datasets for chromatin accessibility (FAIRE-seq) and the enhancer mark H3K27ac that reveal the highly dynamic nature of distal gene regulation during neurogenesis, which gets progressively restricted to distinct genomic regions as neurons acquire a post-mitotic, terminally differentiated state. We further find that the distal accessible and active regions serve as target sites for distinct transcription factors that function in a stage-specific manner to contribute to the transcriptional program underlying neuronal commitment and maturation. Mature neurons respond to a sustained activity of NMDA receptors by epigenetic reprogramming at a large number of distal regulatory regions as well as dramatic reorganization of super-enhancers. Such massive remodeling of distal regulatory landscape in turn results in a transcriptome that confers a transient loss of neuronal identity and gain of cellular plasticity. Furthermore, NMDA receptor activity also induces many novel pro-survival genes that function in neuroprotective pathways. Taken together, these findings reveal the dynamics of the distal regulatory landscape during neurogenesis and uncover novel regulatory elements that function in concert with epigenetic mechanisms and transcription factors to generate the transcriptome underlying neuronal development and activity. Published by Cold Spring Harbor Laboratory Press.
    Genome Research 07/2015; 25(9). DOI:10.1101/gr.190926.115 · 14.63 Impact Factor
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    • "Innate immune signaling molecules in the brain appear to contribute to both brain health and pathology. Indeed, recent studies find that MHC molecules contribute not only to most neurodegenerative diseases (Gage 2002; Glass et al. 2010) as well as alcohol and drug dependence (Crews 2012) but are also critically involved in brain development (Huh et al. 2000). Within the brain microglia, innate immune cytokines, such as TNFα, IL-1β, and HMGB1 as well as TLRs, purinergic receptors (e.g., P2X7), various cytokine receptors, and innate immune proteases and oxidases, all amplify Fig. 2 High-mobility group box 1 (HMGB1) is actively and/or passively released leading to multiple signaling pathways. "
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    Psychopharmacology 03/2015; DOI:10.1007/s00213-015-3906-1 · 3.88 Impact Factor
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    • "MHCI proteins are particularly expressed in neurons of the lateral geniculate nucleus of the thalamus (Zhang et al., 2013b), and also affect axonal and neurite outgrowth of hippocampal neurons in vitro (Bilousova et al., 2012). In addition, knock-out mice for the homologous immune system show increased ocular dominance, as well as aberrant patterns of Long-Term Potentiation (LTP) and Long-Term Depression (LTD) in the hippocampus (Datwani et al., 2009; Elmer and McAllister, 2012; Huh et al., 2000). As these observations indicate effects of the MHC on thalamus and hippocampus development and function, the possibility also arises that the MHC is involved in dysfunction linked to these structures (Lee et al., 2014; McAllister, 2014). "
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    ABSTRACT: Genes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to schizophrenia, while volumetric changes of the thalamus and hippocampus have also been linked to schizophrenia. We therefore investigated whether common variants of the HLA would affect volumetric variation of the thalamus and hippocampus. We analyzed thalamus and hippocampus volumes, as measured using structural magnetic resonance imaging, in 1.265 healthy participants. These participants had also been genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. We imputed genotypes for single nucleotide polymorphisms at high density across the HLA locus, as well as HLA allotypes and HLA amino acids, by use of a reference population dataset that was specifically targeted to the HLA region. We detected a significant association of the SNP rs17194174 with thalamus volume (nominal P=0.0000017, corrected P=0.0039), as well as additional SNPs within the same region of linkage disequilibrium. This effect was largely lateralized to the left thalamus and is localized within a genomic region previously associated with schizophrenia. The associated SNPs are also clustered within a potential regulatory element, and a region of linkage disequilibrium that spans genes expressed in the thalamus, including HLA-A. Our data indicate that genetic variation within the HLA region influences the volume and asymmetry of the human thalamus. The molecular mechanisms underlying this association may relate to HLA influences on susceptibility to schizophrenia. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 02/2015; 46. DOI:10.1016/j.bbi.2015.02.021 · 5.89 Impact Factor
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