Article

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

ABSTRACT

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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    • "This study also identified significant cell-type-specific differences in MHCI gene expression within the hippocampus. These differences may be relevant to phenotypes that are restricted to certain regions of the hippocampus in systemically MHCI-deficient mice, such as increased synapse number, which is seen in area CA3, but not area CA1 (DixonSalazar et al., 2014), and synaptic transmission and plasticity, which are altered at synapses made onto CA1 pyramidal cells by CA3 pyramidal cells (Fourgeaud et al., 2010;Huh et al., 2000;Nelson et al., 2013). The current studies identified nine MHCI genes which could be involved in the regulation of synaptic transmission and plasticity at the CA1/CA3 synapse, because they are expressed in pre-and/or post-synaptic cells at that synapse. "
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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.
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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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    Preview · Article · Jul 2015 · Genome Research
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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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