Classical MHCI Molecules Regulate Retinogeniculate Refinement and Limit Ocular Dominance Plasticity

Abstract

Major histocompatibility complex Class I (MHCI) genes were discovered unexpectedly in healthy CNS neurons in a screen for genes regulated by neural activity. In mice lacking just 2 of the 50+ MHCI genes H2-Kb and H2-Db, ocular dominance (OD) plasticity is enhanced. Mice lacking PirB, an MHCI receptor, have a similar phenotype. H2-Kb and H2-Db are expressed not only in visual cortex, but also in lateral geniculate nucleus (LGN) where protein localization correlates strongly with synaptic markers and complement protein C1q. In KbDb-/- mice developmental refinement of retinogeniculate projections is impaired, similar to C1q-/- mice. These phenotypes in KbDb-/- mice are strikingly similar to those in β2m-/-TAP1-/- mice, which lack cell surface expression of all MHCIs, implying that H2-Kb and H2-Db can account for observed changes in synapse plasticity. H2-Kb and H2-Db ligands, signaling via neuronal MHCI receptors, may enable activity-dependent remodeling of brain circuits during developmental critical periods.

Differential but Competitive Binding of Nogo Protein and Class I Major Histocompatibility Complex (MHCI) to the PIR-B Ectodomain Provides an Inhibition of Cells

“…Our present observation of a Nogo-mediated inhibitory effect on mast cell function, together with the RT-PCR detection of Nogo/MAG/ OMgp mRNAs, suggests that Nogo, and potentially MAG and OMgp as well, have a physiological impact on the immune system. Conversely, in the neuronal system, one may immediately speculate that PIR-B-mediated inhibition of neurite regeneration (13) and neural plasticity (12) could also be mediated synergistically by Nogo/MAG/OMgp and MHCI (31,32). This scenario, particularly a potential co-expression and co-operation of Nogo/MAG/OMgp and MHCI in the cells, should be examined in detail in the next step toward a full understanding of the mechanism of PIR-B-mediated neuronal regulation.…”

A schizophrenia-associated HLA locus affects thalamus volume and asymmetry

“…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 McAllister, 2014).…”

Learning and memory … and the immune system

“…Several isotypes of this molecular complex are now known to be expressed by neurons in the thalamus, hippocampus, cortex, and cerebellum, along with the accessory molecules CD3z and b2-microglobulin. MHCI staining appears as puncta at synapses and colocalizes with postsynaptic density protein 95 (PSD95) (Goddard et al 2007;Datwani et al 2009). Knockout MHCI (KbDb 2/2 ) mice exhibit a phenotype similar to that of the C1q-deficient mice, showing reduced segregation of ocular inputs in the LGN ).…”