Immune Proteins in Brain Development and Synaptic Plasticity

Boulanger, Lisa M.

doi:10.1016/j.neuron.2009.09.001

Cited by 479 publications

(389 citation statements)

References 118 publications

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“…46,47 Several immune-related molecules have been shown to have pleiotropic functions in the brain that can directly influence synaptic function. 48,49 LAT encodes a transmembrane adaptor protein with a role in the development, activation, and maintenance of T cells. 34 It is modulated by CD247 and ZAP70 tyrosine phosphorylation upon TCR activation and controls signal diversification and amplification.…”

Section: Discussionmentioning

confidence: 99%

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Loviglio

Arbogast

Jønch³

et al. 2017

The American Journal of Human Genetics

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Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

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Section: Discussionmentioning

confidence: 99%

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Loviglio

Arbogast

Jønch³

et al. 2017

The American Journal of Human Genetics

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“…Because cytokines have important developmental effects on modulation of synapse formation and regulation of neurogenesis (Boulanger, 2009;Carpentier et al, 2009;Fourgeaud and Boulanger, 2010) those that appear in the brain subsequent to an inflammation may alter normal developmental processes. Similarly, cytokines have important effects on neuronal excitability and neurotransmitter function (reviewed in Galic et al, 2012) and altering the balance of inhibitory and excitatory activity at a critical period may have important long term effects.…”

Section: Methodological Considerationsmentioning

confidence: 99%

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Rana

Aavani

Pittman

2012

Hormones and Behavior

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Humans are exposed to potentially harmful agents (bacteria, viruses, toxins) throughout our lifespan; the consequences of such exposure can alter central nervous system development. Exposure to immunogens during pregnancy increases the risk of developing neurological disorders such as schizophrenia and autism. Further, sex hormones, such as estrogen, have strong modulatory effects on immune function and have also been implicated in the development of neuropathologies (e.g., schizophrenia and depression). Similarly, animal studies have demonstrated that immunogen exposure in utero or during the neonatal period, at a time when the brain is undergoing maturation, can induce changes in learning and memory, as well as dopaminemediated behaviors in a sex-specific manner. Literature that covers the effects of immunogens on innate immune activation and ultimately the development of the adult brain and behavior is riddled with contradictory findings, and the addition of sex as a factor only adds to the complexity. This review provides evidence that innate immune activation during critical periods of development may have effects on the adult brain in a sex-specific manner. Issues regarding sex bias in research as well as variability in animal models of immune function are discussed.

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“…Given the diversity of infections that show a connection to the spectrum of autism disorders (Boksa, 2010;Libbey et al, 2005), as well as evidence from MIA models that reaction to infection rather than infection itself may lead to autismrelated symptoms (Shi et al, 2003), a possible common etiology may be the influence of the immune system (Gottfried et al, 2015;Lintas et al, 2010;Zhang et al, 2010). Cytokines, small cell-signaling proteins that act as immunomodulatory and endocrine messengers, have been implicated throughout the process of CNS development (Boulanger, 2009;Jones and Thomsen, 2013). The immune cells that produce cytokines following activation are separated into two populations of cells: innate and adaptive.…”

Section: Cytokinesmentioning

confidence: 99%

The Role of the Immune System in Autism Spectrum Disorder

Meltzer

Water

2016

Neuropsychopharmacol

385

293

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Autism is a neurodevelopmental disorder characterized by deficits in communication and social skills as well as repetitive and stereotypical behaviors. While much effort has focused on the identification of genes associated with autism, research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in autism spectrum disorders (ASD). Further, it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions. This review will focus on the two main axes of immune involvement in ASD, namely dysfunction in the prenatal and postnatal periods. During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child. Similarly, the presence of maternally derived anti-brain autoantibodies found in~20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD. The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both maternal and child immune systems, and the role they have in diagnosis and treatment.

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Immune Proteins in Brain Development and Synaptic Plasticity

Cited by 479 publications

References 118 publications

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

The Role of the Immune System in Autism Spectrum Disorder

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