Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder

Segman, Ronnen H.; Meltzer, A; Gross‐Tsur, Varda; Kosov, A; Frisch, Amos; Inbar, E; Darvasi, Ariel; Levy, Sharon; Goltser, T; Weizman, Abraham; Galili-Weisstub, Esti

doi:10.1038/sj.mp.4000919

Cited by 52 publications

(18 citation statements)

References 18 publications

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“…Indeed, IL-1β, TNFα, and IL-6 have been implicated as having roles in synaptic plasticity in the hippocampus (Balschun et al 2004; Goshen and Yirmiya 2009; Schneider et al 1998) and can activate astrocytes that modulate synaptic plasticity. Furthermore, IL-1 receptor antagonist polymorphism has been implicated in ADHD (attention deficit hyperactivity disorder) etiopathogenesis (Segman et al 2002), and disrupted attention has been observed previously in our male CAPs-exposed mice (Allen et al 2013). Furthermore, hippocampal GLU in CAPs-exposed males was positively correlated with hippocampal IL-1β/IL-6, likely indicating a mechanistic link between excitotoxicity and neuroinflammatory responses.…”

Section: Discussionsupporting

confidence: 57%

Early Postnatal Exposure to Ultrafine Particulate Matter Air Pollution: Persistent Ventriculomegaly, Neurochemical Disruption, and Glial Activation Preferentially in Male Mice

Allen¹,

Liu²,

Pelkowski³

et al. 2014

Environ Health Perspect

152

172

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Background: Air pollution has been associated with adverse neurological and behavioral health effects in children and adults. Recent studies link air pollutant exposure to adverse neurodevelopmental outcomes, including increased risk for autism, cognitive decline, ischemic stroke, schizophrenia, and depression.Objectives: We sought to investigate the mechanism(s) by which exposure to ultrafine concentrated ambient particles (CAPs) adversely influences central nervous system (CNS) development.Methods: We exposed C57BL6/J mice to ultrafine (< 100 nm) CAPs using the Harvard University Concentrated Ambient Particle System or to filtered air on postnatal days (PNDs) 4–7 and 10–13, and the animals were euthanized either 24 hr or 40 days after cessation of exposure. Another group of males was exposed at PND270, and lateral ventricle area, glial activation, CNS cytokines, and monoamine and amino acid neurotransmitters were quantified.Results: We observed ventriculomegaly (i.e., lateral ventricle dilation) preferentially in male mice exposed to CAPs, and it persisted through young adulthood. In addition, CAPs-exposed males generally showed decreases in developmentally important CNS cytokines, whereas in CAPs-exposed females, we observed a neuroinflammatory response as indicated by increases in CNS cytokines. We also saw changes in CNS neurotransmitters and glial activation across multiple brain regions in a sex-dependent manner and increased hippocampal glutamate in CAPs-exposed males.Conclusions: We observed brain region– and sex-dependent alterations in cytokines and neurotransmitters in both male and female CAPs-exposed mice. Lateral ventricle dilation (i.e., ventriculomegaly) was observed only in CAPs-exposed male mice. Ventriculomegaly is a neuropathology that has been associated with poor neurodevelopmental outcome, autism, and schizophrenia. Our findings suggest alteration of developmentally important neurochemicals and lateral ventricle dilation may be mechanistically related to observations linking ambient air pollutant exposure and adverse neurological/neurodevelopmental outcomes in humans.Citation: Allen JL, Liu X, Pelkowski S, Palmer B, Conrad K, Oberdörster G, Weston D, Mayer-Pröschel M, Cory-Slechta DA. 2014. Early postnatal exposure to ultrafine particulate matter air pollution: persistent ventriculomegaly, neurochemical disruption, and glial activation preferentially in male mice. Environ Health Perspect 122:939–945; http://dx.doi.org/10.1289/ehp.1307984

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Section: Discussionsupporting

confidence: 57%

Early Postnatal Exposure to Ultrafine Particulate Matter Air Pollution: Persistent Ventriculomegaly, Neurochemical Disruption, and Glial Activation Preferentially in Male Mice

Allen¹,

Liu²,

Pelkowski³

et al. 2014

Environ Health Perspect

152

172

View full text Add to dashboard Cite

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“…In contrast, intracerebral injection of IL-1RA worsened learning and memory in a variety of animal models [47,48] and, blocking of the IL-1ß receptor by IL-1RA during the LTP process in the hippocampus, impaired the maintenance of LTP [49,50]. Some studies have also explored the polymorphic variations of IL-1RA [51,52] in association with attention deficit hyperactivity disorder, but with conflicting results.…”

Section: Id Patients Controlsmentioning

confidence: 86%

Involvement of IL-6 and IL-1 receptor antagonist on intellectual disability

et al. 2014

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Imbalances in the regulation of pro-inflammatory cytokines have been increasingly correlated with several neurodevelopmental disorders and their role in neuronal development is being investigated. To assess the possible influence of cytokines on the onset of intellectual disability (ID), we studied the polymorphisms of thirteen proinflammatory cytokine genes in 81 patients and 61 healthy controls. We demonstrated a significant association of interleukin-6 (IL-6) single-nucleotide polymorphism (SNP) (-174 G/C and nt565 G/A), and interleukin-1 receptor antagonist (IL-1RA) (Mspa-I 11100) SNP with ID. Moreover, the IL-6 SNPs is an unfavorable genetic predisposition for females. The evaluation of circulating levels of IL-6 and IL-1RA showed that the serum concentrations of IL-6 were significantly higher in ID patients than in controls. These data suggest that functional cytokine gene polymorphisms may influence the development of ID.

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“…The IL-1RA is a molecule that competes for receptor binding with IL-1a and IL-1b, blocking their role in immune activation. Polymorphisms in IL-1Ra gene, IL1RN, have been directly associated with ADHD (Segman et al 2002). For the inheritance of alleles of an intronic 86-bp VNTR polymorphism, investigators reported significant evidence for biased transmission of the 4-repeat allele.…”

Section: Genetics Of Adhd and Inflammation Signallingmentioning

confidence: 99%

Inflammation: good or bad for ADHD?

Donev

Thome

2010

ADHD Atten Def Hyp Disord

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Attention deficit hyperactivity disorder (ADHD) is characterised by the typical behavioural core symptoms of inattentiveness, hyperactivity and impulsiveness. ADHD is a usually chronic health conditions, mostly diagnosed in childhood, creating a significant challenge for youth, their families and professionals who treat it. This disorder requires long-term treatments, including psychotherapeutic and pharmacological interventions, which in some cases may lead to adverse effects. Understanding the mechanism by which ADHD risk factors affect the biochemical processes in the human brain and consequentially the behaviour will help to identify novel targets for the development of therapeutics with less adverse results and better efficacy including higher responder rates. Although inflammatory responses in the brain have been recognised for years as critical in neurodegeneration and behaviour in a number of neurological and psychiatric disorders, their role for the development, treatment and prevention of ADHD has been so far largely overlooked, although historically, ADHD symptoms were initially observed in patients who survived an ONJ infection, i.e. inflammation. In this review, we discuss the interrelationship between different ADHD risk factors and inflammation with respect to the triggered molecular mechanisms and the contribution they are likely to have to this disorder. This paper provides a rationale for future studies on ADHD with an intent to inspiring the development of new agents for a more efficient management of this disorder.

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Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder

Abstract: Keywords: attention deficit hyperactivity disorder; ADHD; interleukin-1 receptor antagonist gene; transmission disequilibrium test

Cited by 52 publications

References 18 publications

Early Postnatal Exposure to Ultrafine Particulate Matter Air Pollution: Persistent Ventriculomegaly, Neurochemical Disruption, and Glial Activation Preferentially in Male Mice

Early Postnatal Exposure to Ultrafine Particulate Matter Air Pollution: Persistent Ventriculomegaly, Neurochemical Disruption, and Glial Activation Preferentially in Male Mice

Involvement of IL-6 and IL-1 receptor antagonist on intellectual disability

Inflammation: good or bad for ADHD?

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