Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization

Bilousova, Tina; Dang, Hung; Xu, Willem; Gustafson, Sarah; Jin, Yingli; Wickramasinghe, Lalinda; Won, Tony; Bobarnac, Gabriela; Middleton, Blake; Tian, Jide; Kaufman, Daniel L.

doi:10.1016/j.jneuroim.2012.03.008

Cited by 38 publications

(40 citation statements)

References 55 publications

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“…MHCI does regulate the earliest steps of neuronal differentiation—neuronal polarization and neurite outgrowth. MHCI controls the extension and differentiation of neurites from very young hippocampal neurons in vitro (62). Target-derived, secreted or recombinant MHCI protein also negatively regulates axon extension from retinal explants (63, 64) or cultured dorsal root ganglia (65).…”

Section: Mhci In the Cnsmentioning

confidence: 99%

Major Histocompatibility Complex I in Brain Development and Schizophrenia

McAllister

2014

Biological Psychiatry

111

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Although the etiology of schizophrenia (SZ) remains unknown, it is increasingly clear that immune dysregulation plays a central role. Genome-wide association studies reproducibly indicate an association of SZ with immune genes within the major histocompatibility complex (MHC). Moreover, environmental factors that increase risk for SZ, such as maternal infection, alter peripheral immune responses as well as the expression of immune molecules in the brain. MHCI molecules may mediate both genetic and environmental contributions to SZ through direct effects on brain development, in addition to mediating immunity. MHCI molecules are expressed on neurons in the central nervous system (CNS) throughout development and into adulthood, where they regulate many aspects of brain development including neurite outgrowth, synapse formation and function, long-term and homeostatic plasticity, and activity-dependent synaptic refinement. This review summarizes our current understanding of MHCI expression and function in the developing brain, as well as its involvement in maternal immune activation, from the perspective of how these roles for MHCI molecules might contribute to the pathogenesis of SZ.

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Section: Mhci In the Cnsmentioning

confidence: 99%

Major Histocompatibility Complex I in Brain Development and Schizophrenia

McAllister

2014

Biological Psychiatry

111

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“…MHCI proteins are expressed in a brain tissue-specific and developmental stage-specific manner (Liu et al, 2013;Zhang et al, 2013a), and may be major actors in developmental synaptic pruning, which is dependent on neuronal activity (Glynn et al, 2011;Lee et al, 2014). 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).…”

Section: Introductionmentioning

confidence: 99%

A schizophrenia-associated HLA locus affects thalamus volume and asymmetry

Brucato

Guadalupe

Franke

et al. 2015

Brain, Behavior, and Immunity

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a b s t r a c tGenes 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 analysed 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.

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“…Although MHC class I is best-known for its role in adaptive immunity, MHC class I also has important roles in the normal, healthy developing and adult brain (e.g., Huh et al 2000;Loconto et al 2003;Leinders-Zufall et al 2004;Goddard et al 2007;Datwani et al 2009;Glynn et al 2011;Washburn et al 2011;Bilousova et al 2012;Chacon and Boulanger 2013; for reviews, see Boulanger et al 2001;Boulanger and Shatz 2004;Boulanger 2009;McAllister and van de Water 2009;Shatz 2009;Elmer and McAllister 2012). MHC class I mRNA is highly expressed in sites of ongoing adult plasticity, including adult hippocampus (Corriveau et al 1998;Huh et al 2000), where it is present in dendrites of CA1 pyramidal neurons (Zhong et al 2006).…”

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confidence: 99%

MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression

et al. 2013

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Memory impairment is a common feature of conditions that involve changes in inflammatory signaling in the brain, including traumatic brain injury, infection, neurodegenerative disorders, and normal aging. However, the causal importance of inflammatory mediators in cognitive impairments in these conditions remains unclear. Here we show that specific immune proteins, members of the major histocompatibility complex class I (MHC class I), are essential for normal hippocampus-dependent memory, and are specifically required for NMDAR-dependent forms of long-term depression (LTD) in the healthy adult hippocampus. In b2m 2/2 TAP 2/2 mice, which lack stable cell-surface expression of most MHC class I proteins, NMDAR-dependent LTD in area CA1 of adult hippocampus is abolished, while NMDAR-independent forms of potentiation, facilitation, and depression are unaffected. Altered NMDAR-dependent synaptic plasticity in the hippocampus of b2m 2/2 TAP 2/2 mice is accompanied by pervasive deficits in hippocampus-dependent memory, including contextual fear memory, object recognition memory, and social recognition memory. Thus normal MHC class I expression is essential for NMDAR-dependent hippocampal synaptic depression and hippocampus-dependent memory. These results suggest that changes in MHC class I expression could be an unexpected cause of disrupted synaptic plasticity and cognitive deficits in the aging, damaged, and diseased brain.

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Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization

Cited by 38 publications

References 55 publications

Major Histocompatibility Complex I in Brain Development and Schizophrenia

Major Histocompatibility Complex I in Brain Development and Schizophrenia

A schizophrenia-associated HLA locus affects thalamus volume and asymmetry

MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression

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