MHC class I modulates NMDA receptor function and AMPA receptor trafficking

Abstract

Proteins of the major histocompatibility complex class I (MHCI) are known for their role in immunity and have recently been implicated in long-term plasticity of excitatory synaptic transmission. However, the mechanisms by which MHCI influences synaptic plasticity remain unknown. Here we show that endogenous MHCI regulates synaptic responses mediated by NMDA-type glutamate receptors (NMDARs) in the mammalian central nervous system (CNS). The AMPA/NMDA ratio is decreased at MHCI-deficient hippocampal synapses, reflecting an increase in NMDAR-mediated currents. This enhanced NMDAR response is not associated with changes in the levels, subunit composition, or gross subcellular distribution of NMDARs. Increased NMDAR-mediated currents in MHCI-deficient neurons are associated with characteristic changes in AMPA receptor trafficking in response to NMDAR activation. Thus, endogenous MHCI tonically inhibits NMDAR function and controls downstream NMDAR-induced AMPA receptor trafficking during the expression of plasticity.immune | GluR | hippocampus P roteins of the major histocompatibility complex class I (MHCI) are best known for their role in adaptive immunity, but several lines of evidence suggest they also have nonimmune functions in neurons (1, 2). MHCI is expressed by healthy neurons in the developing and adult CNS (3-7). Neuronal MHCI mRNA levels are dynamic during development and are regulated by electrical activity (3, 4) and by the cAMP-response element-binding protein (CREB) (8). MHCI protein is enriched in synaptic fractions (4) and is detected in hippocampal dendritic spines, where it colocalizes with PSD-95 (9).Studies in mice genetically deficient for cell-surface MHCI (β2m −/− TAP −/− mice) suggest a role for MHCI in activity-dependent plasticity. In MHCI-deficient mice, NMDA receptor (NMDAR)-dependent hippocampal long-term potentiation (LTP) is enhanced, whereas long-term depression (LTD) is abolished (4). Although the mechanisms by which MHCI mediates immune signaling have been relatively well characterized, nothing is known about how MHCI contributes to NMDAR-dependent plasticity in vitro or in vivo.In the adult hippocampus, plasticity induced by activation of NMDARs is expressed as changes in the trafficking and function of AMPA receptors (AMPARs) (10-13). In current models, the magnitude and kinetics of NMDAR activation determine whether potentiation or depression is induced, with large, transient NMDAR activation causing LTP and smaller, longer-lasting activation causing LTD (14, 15). Therefore, to better understand the role of endogenous MHCI in the induction or expression of synaptic plasticity, we examined the levels, distribution, trafficking, and function of AMPA-and NMDA-type receptors in MHCI-deficient hippocampal neurons.The current experiments reveal an unexpected role for postsynaptic MHCI in controlling NMDAR function. Loss of MHCI causes a drop in the AMPA/NMDA ratio and an enhancement of NMDAR-mediated responses at CA3-CA1 synapses. This enhancement cannot be attributed to changes in th...

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

“…For example, neuronal MHC I has an established role in neuronal plasticity16 via mechanisms involving postsynaptic interactions with glutamate receptors and presynaptic interactions with the immunoreceptor tyrosine‐based inhibitory motif‐containing leukocyte immunoglobulin‐like receptor PirB 64. Neuronal MHC I has also been shown to inhibit glutamatergic receptor function in hippocampal circuits65 and studies in the retinogeniculate system indicate a role for somatic MHC class I in synapse elimination 66, 67. Likewise, in vitro overexpression and knock down experiments have inversely associated MHC I expression with synapse density in cortical neurons 68.…”

Immune Privilege Revisited: The Roles of Neuronal MHC Class I Molecules in Brain Development and Plasticity

“…Furthermore, MHC class I molecules may affect the function of synapses through their effects on neurotransmitter receptors, such as glutamate receptors (Fourgeaud et al 2010). A recent study indicated that MHC class I proteins may regulate trafficking of NMDAR receptors, which parallels their previously described roles in insulin receptor signaling (Arosa et al 2007, Fishman et al 2004, Fourgeaud et al 2010. Interestingly enough, insulin is mediating a non-NMDAR dependent form of LTD in the hippocampus (Ahmadian et al 2004, Collingridge et al 2010, Ge et al 2010, Wang and Linden 2000.…”

“…As the phenotype of CD3 knock-out mice resembles the phenotype of MHC class I deficient mice, it is safe to assume that they may be involved in the same signaling pathway (Xu et al 2010, Huh et al 2000. Furthermore, MHC class I molecules may affect the function of synapses through their effects on neurotransmitter receptors, such as glutamate receptors (Fourgeaud et al 2010). A recent study indicated that MHC class I proteins may regulate trafficking of NMDAR receptors, which parallels their previously described roles in insulin receptor signaling (Arosa et al 2007, Fishman et al 2004, Fourgeaud et al 2010.…”

Impaired Spatial Memory in Mice Lacking CD3ζ Is Associated with Altered NMDA and AMPA Receptors Signaling Independent of T-Cell Deficiency

“…The learning and spatial memory performances of CD3 Ϫ/Ϫ mice were evaluated with the Barnes circular maze test, a hippocampus-dependent cognitive task that requires spatial reference memory (Barnes, 1979;Bach et al, 1995). Both CD3 ϩ/ϩ (n ϭ 8) and CD3 Ϫ/Ϫ (n ϭ 11) mice learned to locate the escape hole with the hidden box during the course of the training period (D1-4), as indicated by a progressive reduction in the time needed to reach the target hole (Fig.…”

“…In addition, CD3 negatively regulates dendritic complexity in retinal ganglion cells and cultured hippocampal neurons (Baudouin et al, 2008;Xu et al, 2010). Synaptic functions were also altered in CD3-deficient mice, which showed a reduced glutamatergic synaptic activity in the retina (Xu et al, 2010) and defects in synaptic plasticity in the hippocampus, as reflected by an enhanced long-term potentiation (LTP) and a lack of long-term depression (Huh et al, 2000;Barco et al, 2005). However, the role of CD3 in synaptic-plasticity-dependent cognitive behavior, in particular in learning and memory, is currently unknown.…”