Bacterial-induced maternal interleukin-17A pathway promotes autistic-like          behaviors in mouse offspring

Yasumatsu, Kanae; Nagao, Jun Ichi; Arita-Morioka, Ken-ichi; Narita, Yuki; Tasaki, Sonoko; Toyoda, Kazuhiro; Ito, Shoko; Kakemoto, Hirofumi; Tanaka, Yoshihiko

doi:10.1538/expanim.19-0156

Cited by 23 publications

(30 citation statements)

References 34 publications

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“…We also found the upregulation of IL-1β in the double transgenic St3gal5- deficient 5xFAD female mice ( Dukhinova et al., 2019 ). The synergistic interaction of abnormal baseline production of IL-1β, IL-6 and TNF in mutants and LPS-induced systemic inflammation is reminiscent of a ‘double hit’ phenomenon ( Carlezon et al., 2019 ; Couch et al, 2013 , 2016 ; Onore et al., 2013 ; Yasumatsu et al., 2020 ) and could explain the exacerbation of the changes in social behavior observed in the St3gal5−/− mice. At the same time, no differences were fund in counts for mononuclear and polymorphonuclear white blood cells between controls and mutants (Ponomarev, unpublished results ).…”

Section: Discussionmentioning

confidence: 99%

ASD-like behaviors, a dysregulated inflammatory response and decreased expression of PLP1 characterize mice deficient for sialyltransferase ST3GAL5

Strekalova

Svirin

Veniaminova

et al. 2021

Brain, Behavior, & Immunity - Health

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Gangliosides are glycosphingolipids, which are abundant in brain, are known to modulate ion channels and cell-to-cell communication. Deficiencies can result in aberrant myelination and altered immune responses, which can give rise to neurodevelopmental psychiatric disorders. However, to date, little mechanistic data is available on how ganglioside deficiencies contribute to the behavioural disorders. In humans, the loss of lactosylceramide-alpha-2,3-sialyltransferase (ST3Gal5) leads to a severe neuropathology, but in ST3Gal5 knock-out ( St3gal5−/− ) mice the absence of GM3 and associated a-, b- and c-series gangliosides is partially compensated by 0-series gangliosides and there is no overt behavioural phenotype. Here, we sought to examine the behavioural and molecular consequences of GM3 loss more closely. Mutants of both sexes exhibited impaired conditioned taste aversion in an inhibitory learning task and anxiety-like behaviours in the open field, moderate motor deficits, abnormal social interactions, excessive grooming and rearing behaviours. Taken together, the aberrant behaviours are suggestive of an autism spectrum disorder (ASD)-like syndrome. Molecular analysis showed decreased gene and protein expression of proteolipid protein-1 ( Plp1 ) and over expression of proinflammatory cytokines, which has been associated with ASD-like syndromes. The inflammatory and behavioural responses to lipopolysaccharide (LPS) were also altered in the St3gal5−/− mice compared to wild-type, which is indicative of the importance of GM3 gangliosides in regulating immune responses. Together, the St3gal5−/− mice display ASD-like behavioural features, altered response to systemic inflammation, signs of hypomyelination and neuroinflammation, which suggests that deficiency in a- and b-series gangliosides could contribute to the development of an ASD-like pathology in humans.

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Section: Discussionmentioning

confidence: 99%

ASD-like behaviors, a dysregulated inflammatory response and decreased expression of PLP1 characterize mice deficient for sialyltransferase ST3GAL5

Strekalova

Svirin

Veniaminova

et al. 2021

Brain, Behavior, & Immunity - Health

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“…Consistent with our findings are impaired social behaviors in Poly I:C-induced MIA offspring [ 29 , 30 ]. Recent findings indicate that IL-17A is a mediator of MIA that reduces social interaction and induces repetitive behaviors in MIA offspring [ 4 , 31 ], suggesting that the elevated plasma IL-17A levels in Mtb -induced MIA offspring most probably evoked repetitive behaviors and a lack of social skills in our study. Additionally, elevated plasma IL-6 levels are associated with ASD-like behaviors.…”

Section: Discussionmentioning

confidence: 52%

“…Previous findings indicate that increased expression of NRXNs reduces GABAergic neurotransmission [42], while overexpression of NLGN1 increases glutamatergic neurotransmission [43], suggesting an excitation/inhibition imbalance in the synapse that can influence behavior. Increased repetitive behaviors were also observed in other MIA offspring [4,29]. The mechanism underlying repetitive behaviors is not clear; however, they are thought to arise from a combination of genetic and environmental factors affecting the cerebellum development [44,45].…”

Section: Discussionmentioning

confidence: 99%

“…Second trimester respiratory infections and bacterial infections increase the risk of NDDs such as ASD [ 2 , 3 ]. The maternal system strikes a balance between immune tolerance of the growing fetus and immune response against invading pathogens [ 4 ]. Maternal immune response to infection triggers production of inflammatory cytokines which can traverse the fetal–placental barrier inducing fetal inflammation that disrupts brain development.…”

Section: Introductionmentioning

confidence: 99%

“…This inflammation persists through postnatal life as evidenced by elevated pro-inflammatory cytokines in the CNS and serum/plasma of ASD patients [ 5 , 6 ]. Maternal infections of Poly I:C, LPS, influenza, C. rectus and L. monocytogenes alter cytokine levels in the placenta, amniotic fluid, fetal brain and plasma [ 4 , 7 , 8 , 9 , 10 ]. Cytokines mediate neuro-immune communication, and they also regulate neurogenesis and synaptic plasticity; hence, an imbalance in cytokine levels during development can be detrimental to the developing brain.…”

Section: Introductionmentioning

confidence: 99%

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Mycobacterium tuberculosis-Induced Maternal Immune Activation Promotes Autism-Like Phenotype in Infected Mice Offspring

Manjeese

Mvubu

Steyn

et al. 2021

IJERPH

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The maternal system’s exposure to pathogens during pregnancy influences fetal brain development causing a persistent inflammation characterized by elevated pro-inflammatory cytokine levels in offspring. Mycobacterium tuberculosis (Mtb) is a global pathogen that causes tuberculosis, a pandemic responsible for health and economic burdens. Although it is known that maternal infections increase the risk of autism spectrum disorder (ASD), it is not known whether Mtb infection is sufficient to induce ASD associated behaviors, immune dysregulation and altered expression of synaptic regulatory genes. The current study infected pregnant Balb/c mice with Mtb H37Rv and valproic acid (VPA) individually and in combination. Plasma cytokine profiles were measured in offspring using the Bio-plex Th17 pro mouse cytokine panel. Mtb infection increased plasma interleukin (IL)-6 and IL-17A, while tumor necrosis factor alpha (TNF-α), interferon (IFN)-γ and IL-1β were reduced when compared with saline. Mtb-induced maternal immune activation (MIA) offspring displayed increased grooming behavior. The study also revealed dysregulation in gene expression of synaptic molecules in the cerebellum. MIA rescued the VPA-induced effects on self-grooming and social interaction behaviors. Our finding therefore highlights a potential role of Mtb as a MIA agent that can potentially contribute to ASD.

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Prenatal epigenetic factors are predisposing for neurodevelopmental disorders—Considering placenta as a model

Durbagula

Korlimarla

Ravikumar

et al. 2022

Birth Defects Research

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The heterogeneous characteristics of neurodevelopmental disorders (NDDs) have resulted in varied perspectives on their causation. The biology behind the phenotypic heterogeneity in NDDs is not yet well‐defined, but a strong genetic basis has become well accepted as causal for NDDs. Alongside this, there is growing focus on epigenetic mechanisms. The evidence mounting for in‐utero origins of NDDs has promoted research focused on epigenetic mechanisms that impact genes that program early brain development. Considering that placenta is a vital organ, this review emphasizes the prenatal factors and their effects on epigenetic changes influencing the normal functioning of the placenta, and factors mediating pathology in the developing fetus. Overall, it is an attempt to bring focus on the hypothesis that “Prenatal epigenetic factors in the placenta could be predisposing to NDDs (with special interest on autism spectrum disorders).” This review finds growing evidence for epigenetic modifications in the placenta that affect glucocorticoid, nutrient, and immune signaling pathways, eventually impacting fetal brain development. This evidence largely comes from animal models. Given the multicellular nature of placenta, we conclude that, there is a need for placental research focused on employing single‐cell approaches and genome‐wide methylation profiles to bring insights into specific molecular pathways in the placenta that regulate early brain development.

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Bacterial-induced maternal interleukin-17A pathway promotes autistic-like behaviors in mouse offspring

Cited by 23 publications

References 34 publications

ASD-like behaviors, a dysregulated inflammatory response and decreased expression of PLP1 characterize mice deficient for sialyltransferase ST3GAL5

ASD-like behaviors, a dysregulated inflammatory response and decreased expression of PLP1 characterize mice deficient for sialyltransferase ST3GAL5

Mycobacterium tuberculosis-Induced Maternal Immune Activation Promotes Autism-Like Phenotype in Infected Mice Offspring

Prenatal epigenetic factors are predisposing for neurodevelopmental disorders—Considering placenta as a model

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