MHC Class I Limits Hippocampal Synapse Density by Inhibiting Neuronal Insulin Receptor Signaling

Dixon‐Salazar, Tracy; Fourgeaud, Lawrence; Tyler, Carolyn M.; Poole, Julianna R.; Park, Joseph J.; Boulanger, Lisa M.

doi:10.1523/jneurosci.4642-12.2014

Cited by 51 publications

(69 citation statements)

References 75 publications

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“…We have identified a pathway dependent on Aβ 1-42 oligomers and ERK1/2 that disturbs insulin signaling pathway and glycogen storage in astrocytes. As previously reported, insulin signaling participates in synapse plasticity, learning and memory in neurons, the impairment of which is associated with the development of AD (Dixon-Salazar et al, 2014;Talbot et al, 2012). However, insulin signaling may also participate in the regulation of glutamate clearance, energy metabolism and anti-oxidation in astrocytes (Li et al, 2006;Brown and Ransom, 2007;Ji et al, 2011;Genis et al, 2014), all of which are essential for normal functions and survival of neuron.…”

Section: Discussionmentioning

confidence: 79%

“…Insulin plays a crucial role in the regulation of brain glucose metabolism, neurotransmission, learning and memory, synapse plasticity and anti-apoptosis (McNay et al, 2010;McNay and Recknagel, 2011;Dixon-Salazar et al, 2014). Accumulating evidence indicates that hippocampi in brains of AD patients exhibit defective insulin signaling with altered levels and cellular distribution of insulin receptors and inhibitory serine phosphorylation of insulin receptor substrate-1 (IRS-1) (Steen et al, 2005;Moloney et al, 2010;Bomfim et al, 2012;Talbot et al, 2012;Lourenco et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Amyloid β oligomer-induced ERK1/2-dependent serine 636/639 phosphorylation of insulin receptor substrate-1 impairs insulin signaling and glycogen storage in human astrocytes

Zhang

Tang

et al. 2015

Gene

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Amyloid β oligomer-induced ERK1/2-dependent serine 636/639 phosphorylation of insulin receptor substrate-1 impairs insulin signaling and glycogen storage in human astrocytes

Zhang

Tang

et al. 2015

Gene

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“…For example, several mutations and abnormalities that are associated with various neurodevelopmental syndromes, such as MeCP2 (methyl CpG binding protein 2, which causes Rett syndrome in humans; Samaco and Neul, 2011), neurexin and neuroligins (associated with ASD; Buxbaum, 2009), FMRP (fragile X mental retardation protein; Abrahams and Geschwind, 2008), and altered immune signaling (also found in ASD; Cohly and Panja, 2005) all result in abnormal synaptic development and/or neural circuit formation in rodents (Samaco and Neul, 2011;Bhakar et al, 2012;Dixon-Salazar et al, 2014). Similarly in Xenopus tadpoles, disruptions of MeCP2 and neurexin/neuroligin signaling also result in abnormal dendritic morphology and synaptic connectivity in optic tectal neurons (Chen et al, 2010;Marshak et al, 2012). Altered levels of proinflammatory cytokines also cause abnormal dendritic development and hyperconnectivity in the Xenopus tadpole tectum (Lee et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Valproate-Induced Neurodevelopmental Deficits inXenopus laevisTadpoles

James

Ramirez-Vizcarrondo

et al. 2015

J. Neurosci.

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Autism spectrum disorder (ASD) is increasingly thought to result from low-level deficits in synaptic development and neural circuit formation that cascade into more complex cognitive symptoms. However, the link between synaptic dysfunction and behavior is not well understood. By comparing the effects of abnormal circuit formation and behavioral outcomes across different species, it should be possible to pinpoint the conserved fundamental processes that result in disease. Here we use a novel model for neurodevelopmental disorders in which we expose Xenopus laevis tadpoles to valproic acid (VPA) during a critical time point in brain development at which neurogenesis and neural circuit formation required for sensory processing are occurring. VPA is a commonly prescribed antiepileptic drug with known teratogenic effects. In utero exposure to VPA in humans or rodents results in a higher incidence of ASD or ASD-like behavior later in life. We find that tadpoles exposed to VPA have abnormal sensorimotor and schooling behavior that is accompanied by hyperconnected neural networks in the optic tectum, increased excitatory and inhibitory synaptic drive, elevated levels of spontaneous synaptic activity, and decreased neuronal intrinsic excitability. Consistent with these findings, VPA-treated tadpoles also have increased seizure susceptibility and decreased acoustic startle habituation. These findings indicate that the effects of VPA are remarkably conserved across vertebrate species and that changes in neural circuitry resulting from abnormal developmental pruning can cascade into higher-level behavioral deficits.

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“…MHC class I forms a complex with the insulin receptor in brain lysates, and unmasks a cytoplasmic epitope of the insulin receptor. In the absence of MHC class I, insulin receptors are constitutively active, and pharmacologically rescuing downstream insulin receptor signaling rescues synapse density in the hippocampus of these mutants (Dixon-Salazar et al, 2014). These studies suggest that MHC class I helps ensure proper hippocampal circuit formation through interactions with non-immunoreceptor proteins in the mammalian brain.…”

Section: Molecular Mechanisms Of Mhc Class I's Nonimmune Functions Inmentioning

confidence: 84%

“…Loss of MHC class I also de-represses signaling mediated by the insulin receptor, a known synapse-promoting factor, and inhibiting insulin receptor signaling in MHC class I-deficient mice rescues synapse density in the hippocampus. Thus endogenous MHC class I ensures appropriate synapse density in the hippocampus by inhibiting the synapsepromoting effects of the insulin receptor (Dixon-Salazar et al, 2014).…”

Section: Mhc Class I Negatively Regulates Synapse Densitymentioning

confidence: 99%

New Roles for MHC Class I Immune Molecules in the Healthy and Diseased Nervous System

Tyler

Boulanger

2014

Encyclopedia of Life Sciences

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Proteins of the major histocompatibility complex class I (MHC class I) are best known for their central role in the immune response. However, accumulating evidence shows that MHC class I proteins also have nonimmune roles in the healthy nervous system. MHC class I is expressed by developing and adult neurons, and is required for the proper establishment, function and modification of synaptic connections. The newly discovered, critical functions of MHC class I in the healthy nervous system suggest that MHC class I could directly link the immune response to changes in brain structure and function in diverse neurological disorders. Key Concepts: MHC class I is expressed by developing and mature neurons in the healthy nervous system. Endogenous MHC class I limits neurite outgrowth, limits synapse density and promotes synapse elimination in multiple brain regions. MHC class I limits synaptic transmission mediated by NMDA‐type glutamate receptors in the hippocampus, regulates NMDAR‐dependent synaptic plasticity, and is required for normal NMDAR‐dependent learning and memory. The receptors and signalling pathways that mediate MHC class I's effects on neurons remain largely unknown. Disruption of the nonimmune functions of MHC class I may be an unexpected contributor to diverse neurological disorders.

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MHC Class I Limits Hippocampal Synapse Density by Inhibiting Neuronal Insulin Receptor Signaling

Cited by 51 publications

References 75 publications

Amyloid β oligomer-induced ERK1/2-dependent serine 636/639 phosphorylation of insulin receptor substrate-1 impairs insulin signaling and glycogen storage in human astrocytes

Amyloid β oligomer-induced ERK1/2-dependent serine 636/639 phosphorylation of insulin receptor substrate-1 impairs insulin signaling and glycogen storage in human astrocytes

Valproate-Induced Neurodevelopmental Deficits inXenopus laevisTadpoles

New Roles for MHC Class I Immune Molecules in the Healthy and Diseased Nervous System

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