Functional Requirement for Class I MHC in CNS Development and Plasticity

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, longterm 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, CD3ζ, 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).The development of precise connections in the CNS is critically dependent on neural activity, which drives the elimination of inappropriate connections and the stabilization of appropriate ones. In the visual system of higher mammals, the refinement of initially imprecise axonal connections requires spontaneously generated activity early in development and visually driven activity later (1-4). Fine-tuning of neural connectivity is thought to result from changes in synaptic strength, driven by patterned impulse activity (1,2,5,6).To identify molecules critical for activity-dependent structural remodeling, we previously conducted an unbiased screen for mRNAs selectively regulated by blocking spontaneously generated activity in the developing cat visual system. This manipulation prevents the remodeling of retinal axons from each eye into layers within the lateral geniculate nucleus (LGN) (7-9). Although many known neural genes were not detectably regulated by activity blockade, this screen revealed to our surprise that members of the class I MHC protein family are expressed by neurons and are regulated by spontaneous and evoked neural activity (10). Neuronal class I MHC expression corresponds to well-characterized times and regions of activity-dependent development and plasticity of CNS connections, including retina, LGN, and hippocampus. Furthermore, the mRNA for CD3ζ [a class I MHC receptor subunit in the immune system (11)] is also expressed by neurons (10), consistent with its interaction with class I MHC during activity-dependent remodeling and plasticity. Although class I MHC is primarily known for its function in cell-mediated immune recognition, the above findings from our differential screen suggest that class I MHC molecules may play roles in structural and synaptic remodeling in the developing and mature CNS.

Ganglioside expression in tissues of mice lackingβ2-microglobulin

“…However, very little is known about the cell type-specific expression of neolacto-series gangliosides in murine organs. Increased expression of ganglioside IV 6 nLc4(C 24 ) in the brain of b 2 M-/-compared with the control b 2 M+/-mice may be related to the role of class I MHC molecules in the central nervous system [3]. It has been shown that class I MHC molecules are expressed by specific sets of neurones that undergo activity-dependent changes [46], and that mice lacking either b 2 M or CD3z exhibit abnormalities in connections between these neurones [3].…”

“…Increased expression of ganglioside IV 6 nLc4(C 24 ) in the brain of b 2 M-/-compared with the control b 2 M+/-mice may be related to the role of class I MHC molecules in the central nervous system [3]. It has been shown that class I MHC molecules are expressed by specific sets of neurones that undergo activity-dependent changes [46], and that mice lacking either b 2 M or CD3z exhibit abnormalities in connections between these neurones [3]. Neolacto-series gangliosides are well characterized in acoustic neurinoma samples [47] and the peripheral nervous system [48] *Density of individual bands was expressed as the percentage of the total density for all bands.…”

“…Lactosylceramide or LacCer, Galß1-4Glcß1-1Cer; gangliotriaosylceramide or GgOse 3 Cer, GalNAcß1-4Galß1-4Glcß1-1Cer; gangliotetraosylceramide or GgOse 4 Cer, Galß1-3GalNAcß1-4Galß1-4Glcß1-1Cer; lacto-N-neotetraosylceramide or nLcOse 4 Cer or nLc4, Galß1-4GlcNAcß1-3Galß1-4Glcß1- 1Cer; lacto-N-norhexaosylceramide or nLcOse 6 Cer or nLc6, Galß1-4GlcNAcß1-3Galß1-4GlcNAcß1-3Galß1- …”

The neuroprotective and neurorescue effects of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson’s disease

“…Bouzat et al (2011) Besides its important effects on the SHH pathway, CEPO might exert its beneficial effects on nerve cells through its action on MHC-I (major histocompatibility complex type I) molecules. MHC-I molecules are involved in nerve plasticity and play an important role in nerve cell recovery by increasing outgrowth of axons in injured neurons (Oliveira et al, 2004;Fu et al, 2010;Huh et al, 2000). In this context, the immunomodulatory effects of CEPO induce stable improvement in neurite outgrowth, which is crucial in restoring the CNS after injury (Fu et al, 2010;Adembri et al, 2008;Schmidt et al, 2008).…”

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

“…The MHC-I (major histocompatibility complex class I) proteins, a key player in adaptive immunity, is enriched in synaptic fractions and the deficiency of which can result in enlarged neural projections [65]. MHC-I can negatively regulate synapse density during the formation of cortical connections via signaling pathways which require MEF2, an ASD candidate gene [66,67].…”