Regulation of CNS synapses by neuronal MHC class I

Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2007; 104(16):6828-33. DOI: 10.1073/pnas.0702023104
Source: PubMed


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 beta2m/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.

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    • "Recently, Paolicelli and collaborators showed that CX 3 CR1 knock-out (KO) mice have fewer microglia in postnatal hippocampus compared to wild type mice at the same age. These findings are consistent with previous data suggesting that immune molecules, such as class I molecules of histocompatibility major complex (MHC1), complement cascade molecules and neuronal pentraxins, contribute to synaptic elimination or strengthening during development (Boulanger, 2009; Corriveau et al., 1998; Datwani et al., 2009; Goddard et al., 2007; Huh et al., 2000; Schafer et al., 2012; Stevens et al., 2007) (Fig. 1). For instance, complement proteins C1q and C3, have emerged as critical mediators of synaptic refinement and plasticity (Schafer et al., 2012; Stephan et al., 2012; Stevens et al., 2007). "
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    ABSTRACT: The central nervous system (CNS) has previously been regarded as an immune-privileged site with the absence of immune cell responses but this dogma was not entirely true. Microglia are the brain innate immune cells and recent findings indicate that they participate both in CNS disease and infection as well as facilitate normal CNS function. Microglia are highly plastic and play integral roles in sculpting the structure of the CNS, refining neuronal circuitry and connectivity, and contribute actively to neuronal plasticity in the healthy brain. Interestingly, psychological stress can perturb the function of microglia in association with an impaired neuronal plasticity and the development of emotional behavior alterations. As a result it seemed important to describe in this review some findings indicating that the stress-induced microglia dysfunction may underlie neuroplasticity deficits associated to many mood disorders. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 01/2015; DOI:10.1016/j.neuropharm.2014.12.034 · 5.11 Impact Factor
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    • "MHC 1 expression has also been detected in the CNS. Its expression is spread across the brain, but of particular interest to ASD, it is expressed in developing and adult hippocampal pyramidal [28] [29] and cerebellar neurons [30] as well as the neuronal synaptic membranes [31]. In line with its expression on synaptic membranes, MHC I is thought to be essential for synapse formation and plasticity [31]. "
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    ABSTRACT: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by deficits in social interactions, communication, and increased stereotypical repetitive behaviors. The immune system plays an important role in neurodevelopment, regulating neuronal proliferation, synapse formation and plasticity, as well as removing apoptotic neurons. Immune dysfunction in ASD has been repeatedly described by many research groups across the globe. Symptoms of immune dysfunction in ASD include neuroinflammation, presence of autoantibodies, increased T cell responses, and enhanced innate NK cell and monocyte immune responses. Moreover these responses are frequently associated with more impairment in core ASD features including impaired social interactions, repetitive behaviors and communication. In mouse models replacing immune components in animals that exhibit autistic relevant features leads to improvement in behavior in these animals. Taken together this research suggests that the immune dysfunction often seen in ASD directly affects aspects of neurodevelopment and neurological processes leading to changes in behavior. Discussion of immune abnormalities in ASD will be the focus of this review. Copyright © 2014. Published by Elsevier B.V.
    Immunology Letters 11/2014; 163(1):49-55. DOI:10.1016/j.imlet.2014.11.006 · 2.51 Impact Factor
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    • "A phenomenon implicated in development and maintenance of neuronal circuitry in the visual system (for review see Higenell and Ruthazer, 2010), the hippocampus, the cerebellum and the cortex (Ribic, 2012). Major histocompatibility complex I expression by developing neurons may be involved in retrograde signaling that regulates synaptic structure (Goddard et al., 2007). Neuronal MHC-I signaling may in some cases require regulators of cellular differentiation (Potthoff and Olson, 2007) known as myocyte enhancer factor 2 transcription factors (Elmer et al., 2013) to eliminate synapses during brain development. "
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    ABSTRACT: Neuronal expression of major histocompatibility complex I (MHC-I) has been implicated in developmental synaptic plasticity and axonal regeneration in the central nervous system (CNS), but recent findings demonstrate that constitutive neuronal MHC-I can also be involved in neurodegenerative diseases by playing a neuroinflammtory role. Recent reports demonstrate its expression in vitro and in human postmortem samples and support a role in neurodegeneration involving proinflammatory cytokines, activated microglia and increased cytosolic oxidative stress. Major histocompatibility complex I may be important for both normal development and pathogenesis of some CNS diseases including Parkinson's.
    Frontiers in Neuroanatomy 10/2014; 8:114. DOI:10.3389/fnana.2014.00114 · 3.54 Impact Factor
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