Immune mediators in the brain and peripheral tissues in autism spectrum disorder

Estes, Myka L.; McAllister, A. Kimberley

doi:10.1038/nrn3978

Cited by 393 publications

(370 citation statements)

References 265 publications

(286 reference statements)

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“…Immune dysfunction (18,(20)(21)(22) and inflammation of the brain (23)(24)(25) are now invoked in the pathogenesis of ASD. However, the stimuli that promote these inflammatory processes in the brain are presently unknown.…”

mentioning

confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

104

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We had reported elevated serum levels of the peptide neurotensin (NT) in children with autism spectrum disorders (ASD). Here, we show that NT stimulates primary human microglia, the resident immune cells of the brain, and the immortalized cell line of human microglia-SV40. NT (10 nM) increases the gene expression and release (P < 0.001) of the proinflammatory cytokine IL-1β and chemokine (C-X-C motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine and chemokine gene expression and release from human microglia. Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be translocated from the cytoplasm to the cell surface, and to be secreted extracellularly. Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown by phosphorylation of its substrates and inhibition of these responses by drugs that prevent mTOR activation. NT-stimulated responses are inhibited by the flavonoid methoxyluteolin (0.1–1 μM). The data provide a link between sortilin and the pathological findings of microglia and inflammation of the brain in ASD. Thus, inhibition of this pathway using methoxyluteolin could provide an effective treatment of ASD.

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mentioning

confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

104

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“…Postmortem studies using brain specimens from depressed suicide victims have revealed epigenetic modifications (methylation abnormalities) in the promoter region of BEGAIN, a gene associated with PSD95 expression (Nagy et al, 2015). In addition, PSD95 engulfment by microglia can lead to excessive complement activation and pruning (Estes and McAllister, 2015). Although specific information is still lacking, it would be tempting to speculate that the movement and clustering of AMPA and NMDA proteins and their binding to stargazin or nitric oxide synthase within the PSD95 complex might be altered during inflammatory activation in mood disorders.…”

Section: Synaptogenesis Gliotransmission and Circuit Integrationmentioning

confidence: 99%

“…The clustering and location of ionotropic receptors within the postsynaptic membrane varies across contexts and time points, and regulates the balance between activation and desensitization of AMPA and NMDA receptors, and thus has the potential to decrease neuroplasticity and increase signaling disarray (Allam et al, 2015;Allam et al, 2012;Ma et al, 2014). PSD95 function is controlled by immune activity in the glial cells such as astrocytes and microglial cells (Torres-Platas et al, 2014b; Torres-Platas et al, 2011) during physiological (normal development) and pathological contexts (Estes and McAllister, 2015). For example, prenatal immune activation using poly(I:C), a preclinical model of prenatal viral exposure implicated in schizophrenia and autism spectrum disorders resulted in pronounced decreases of PSD95 in hippocampal regions associated with prominent behavioral changes (Giovanoli et al, 2016).…”

Section: Synaptogenesis Gliotransmission and Circuit Integrationmentioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

386

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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“…Further, twin and family studies indicate that both genetic and environmental factors, as well as their interplay, influence ASD etiology. [29][30][31][32] Age and gender bias, in combination with limited control over genetic and environmental confounders, are likely to have contributed to earlier mixed findings of RS connectivity in ASD. To this end, discordant monozygotic (MZ) twin pair designs provide excellent methodological control over genetic as well as shared environmental factors, including age, gender and other possible confounding variables such as family background and parental age.…”

Section: Introductionmentioning

confidence: 99%

“…On the basis of our aim to investigate SN and DMN brain connectivity, we extracted functional MRI signal intensity time courses from four ROIs (radius 10 mm) encompassing core hubs within the DMN (PCC [ − 6, − 44,34] and vmPFC [ − 2, 38, − 12]) and the SN (right AI = rAI [39, 23, − 4] and ACC [6,24,32]). The selection of coordinates was based on the peaks of activity yielded by a previous Independent Component Analysis study conducted in typically developed children and adults.…”

Section: Selection Of Regions Of Interestmentioning

confidence: 99%

Alterations in resting state connectivity along the autism trait continuum: a twin study

et al. 2017

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Autism spectrum disorder (ASD) has been found to be associated with alterations in resting state (RS) functional connectivity, including areas forming the default mode network (DMN) and salience network (SN). However, insufficient control for confounding genetic and environmental influences and other methodological issues limit the generalizability of previous findings. Moreover, it has been hypothesized that ASD might be marked by early hyper-connectivity followed by later hypo-connectivity. To date, only a few studies have explicitly tested age-related influences on RS connectivity alterations in ASD. Using a within-twin pair design (N = 150 twins; 8-23 years), we examined altered RS connectivity between core regions of the DMN and SN in relation to autistic trait severity and age in a sample of monozygotic (MZ) and dizygotic (DZ) twins showing typical development, ASD or other neurodevelopmental conditions. Connectivity between core regions of the SN was stronger in twins with higher autistic traits compared to their co-twins. This effect was significant both in the total sample and in MZ twins alone, highlighting the effect of non-shared environmental factors on the link between SN-connectivity and autistic traits. While this link was strongest in children, we did not identify differences between age groups for the SN. In contrast, connectivity between core hubs of the DMN was negatively correlated with autistic traits in adolescents and showed a similar trend in adults but not in children. The results support hypotheses of age-dependent altered RS connectivity in ASD, making altered SN and DMN connectivity promising candidate biomarkers for ASD.Molecular Psychiatry advance online publication, 1 August 2017; doi:10.1038/mp.2017.160 INTRODUCTION Altered patterns of brain connectivity have been suggested as a key neurobiological correlate of the behavioral characteristics of autism spectrum disorder (ASD). However, as findings are inconsistent, the precise brain connectivity characteristics of ASD remain unclear. A large number of resting-state (RS) functional magnetic resonance imaging (MRI) brain connectivity studies have shown a complex pattern of both hypo-and hyper-connectivity in ASD.1-3 Notably, a large multi-site classification study including ASD and typically developing individuals (N = 252, 6-36 years) showed that of the top 100 biomarkers of brain connectivity achieving together 90.8% accuracy, 45% were related to hyperconnectivity and the remaining 55% to hypo-connectivity. 4 It is likely that the observed inconsistencies in classical brain connectivity investigations are limited by methodological issues, such as insufficient control for head motion or the inclusion of global signal regression which can modulate or even invert the direction of functional connectivity differences. [5][6][7] Moreover, gender has recently been shown to modulate the direction of connectivity differences in ASD. 8 In contrast, another study found default mode network (DMN) hypo-connectivity in both genders.

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Immune mediators in the brain and peripheral tissues in autism spectrum disorder

Cited by 393 publications

References 265 publications

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Alterations in resting state connectivity along the autism trait continuum: a twin study

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