Regulation of CNS synapses by neuronal MHC class I

Abstract

Until recently, neurons in the healthy brain were considered immune-privileged because they did not appear to express MHC class I (MHCI). However, MHCI mRNA was found to be regulated by neural activity in the developing visual system and has been detected in other regions of the uninjured brain. Here we show that MHCI regulates aspects of synaptic function in response to activity. MHCI protein is colocalized postsynaptically with PSD-95 in dendrites of hippocampal neurons. In vitro, whole-cell recordings of hippocampal neurons from ␤2m/TAP1 knockout (KO) mice, which have reduced MHCI surface levels, indicate a 40% increase in mini-EPSC (mEPSC) frequency. mEPSC frequency is also increased 100% in layer 4 cortical neurons. Similarly, in KO hippocampal cultures, there is a modest increase in the size of presynaptic boutons relative to WT, whereas postsynaptic parameters (PSD-95 puncta size and mEPSC amplitude) are normal. In EM of intact hippocampus, KO synapses show a corresponding increase in vesicles number. Finally, KO neurons in vitro fail to respond normally to TTX treatment by scaling up synaptic parameters. Together, these results suggest that postsynaptically localized MHCl acts in homeostatic regulation of synaptic function and morphology during development and in response to activity blockade. The results also imply that MHCI acts retrogradely across the synapse to translate activity into lasting change in structure.homeostatic ͉ neuron ͉ plasticity ͉ synapsin ͉ PSD-95 E xperience transduced into neural activity is required for proper brain development (1). The process by which neural activity remodels synaptic connections during development is termed ''activity-dependent plasticity,'' in which electrical signals induce specific patterns of gene transcription to alter synaptic properties and structural connectivity. Genes including BDNF and CamKII are known to be critical for this plasticity (2-4); however, many other molecules are likely involved as well.MHC class I (MHCI) family members are well known for their roles in cellular immunity, but a neuronal function has not been generally appreciated. In the immune system, MHCI genes act in concert with T cell receptors to discriminate self-versus non-self-proteins. The CNS was considered ''immune privileged,'' in part, because it was thought that healthy neurons do not express MHCI protein (5, 6). Recently, MHCI gene family members have been found at low levels in CNS neurons (7-11). MHCI mRNA is expressed and regulated in cortical and thalamic neurons during development and is down-regulated by chronic activity blockade with Tetrodotoxin (TTX) in vivo (7). MHCI is also a downstream target of the transcription factor CREB, required for Hebbian synaptic plasticity (8,12,13). MHCI is thus implicated in several forms of activity-dependent synaptic plasticity.The MHCI gene family includes Ͼ70 members in rodents (14). The proteins encoded are heavy chains comprising the largest portion of the MHCI protein complex. Functional MHCI is usually a trimer consisting...

Expression of Nonclassical Class I Major Histocompatibility Genes Defines a Tripartite Organization of the Mouse Vomeronasal System

“…However, over the past decade, class I Mhc molecules have been implicated in the refinement of synapse formation and plasticity in the visual system and the hippocampus (Corriveau et al, 1998;Huh et al, 2000;Boulanger and Shatz, 2004) and in the maintenance of synapses of motoneurons (Oliveira et al, 2004). Mhc molecules are localized postsynaptically in dendrites of hippocampal neurons and appear to be involved in homeostatic regulation of synaptic function and morphology in response to neural activity (Goddard et al, 2007). A candidate Mhc class I receptor is expressed in subsets of neurons throughout the brain (Syken et al, 2006).…”

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

“…We have proposed that this mechanism underlies the injury of demyelinated axons in multiple sclerosis (MS) 1, 2, 4, 10. Evidence also suggests that MHC I is involved with synaptic pruning during cortical development12, 13, 14, 16, 17, 18, 19, 20, 21 and following injury22, 23, 24, 25 and contributes to neuronal plasticity 16, 17, 26, 27. These findings also suggest that retrogradely induced MHC class I may contribute to the diffuse synaptopathy observed in MS and other neurodegenerative diseases 28, 29, 30, 31, 32, 33, 34, 35.…”

H2-K b and H2-D b regulate cerebellar long-term depression and limit motor learning

“…It was not previously known which of the more than 50 MHCI family members might contribute to neuronal phenotypes observed in ␤2m Ϫ/Ϫ and/or ␤2m Ϫ/Ϫ TAP1 Ϫ/Ϫ mice (4,7,8,12). The fact that this large family of molecules is highly polymorphic in natural populations (1,2), and that the expression pattern of individual family members varies throughout the CNS (4), raises the intriguing possibility that particular MHCI molecules, as well as cognate receptors, may play specific roles in regulating the capacity of distinct brain circuits to change with learning and experience.…”

“…Initial efforts to explore the function of MHCI in the CNS and olfactory bulb used ␤2m-and/or TAP1-deficient mice, which have markedly reduced cell surface expression of many, if not all, MHCI molecules (10,11). These studies implicate neuronal MHCI in activity-dependent synaptic plasticity in visual and hippocampal circuits (4,8). Additional studies of ␤2m Ϫ/Ϫ mice have revealed that the stability of inhibitory synapses onto spinal motor neurons is altered after axotomy (12), and these mice also have defects in pheromone receptor localization and male-male aggressive behavior (7).…”

“…Although MHCI was not thought to be expressed in the healthy brain, recent discoveries have reported both classical and nonclassical MHCI expression in subsets of neurons, including cerebral cortex, hippocampus (3, 4), motoneurons (5), and the mouse vomeronasal organ (6, 7). MHCI protein has been localized in neuronal dendrites and synapses (3,8), and the non-classical H2-M10 family is co-expressed with the V2R pheromone receptors (6, 7), possibly related to MHCI-binding peptides, which have been linked to social recognition (9). Initial efforts to explore the function of MHCI in the CNS and olfactory bulb used ␤2m-and/or TAP1-deficient mice, which have markedly reduced cell surface expression of many, if not all, MHCI molecules (10, 11).…”