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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    • "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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    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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