MCP-1 Signaling Disrupts Social Behavior by Modulating Brain Volumetric Changes and Microglia Morphology

Maldonado-Ruiz, Roger; Trujillo-Villarreal, Luis A; Montalvo-Martínez, Larisa; Mercado-Gómez, Octavio Fabián; Arriaga-Ávila, Virginia; Garza-Ocañas, Lourdes; Ortı́z-López, Rocio; Garza-Villarreal, Eduardo A.; Guevara‐Guzmán, Rosalinda; Camacho‐Morales, Alberto

doi:10.1007/s12035-021-02649-7

Cited by 22 publications

(12 citation statements)

References 64 publications

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“…Appreciating for the contribution of Michael V. Lombardo et al, who recruited a total of 188 toddles, including 81 individuals of ASD around 3-4 years [11], we found that the myeloid cells were statistically signi cant boosted and activated, particularly neutrophils (Fig. 2C-D) in the peripheral blood of autism patients.…”

Section: Discussionsupporting

confidence: 58%

“…Admittedly, ASD patients and ASD model rodent display immune dysfunction [7][8][9]. The vital pathways enriched in ammatory regulators such as interleukin-17A (IL-17A), interleukin-6 (IL-6) and MCP-1, were notably noticed presently [9][10][11]. The expression level of the ASD-risk genes co-expressed in the peripheral blood leukocytes and the brain tissues were proved associated with multivariate functional neuroimaging (fMRI) response to speech between typically developing toddlers and toddlers with ASD [12].…”

Section: Introductionmentioning

confidence: 99%

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The early postnatal activation of A2ARs protects BTBR mice against autism related behavior

Zhou

Yang

et al. 2022

Preprint

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Background: Studies mainly focused on the immediate effect of drugs on Autism spectrum disorders (ASD), the complex heterogeneous neurodevelopmental disorders, which been proved involved with the chronic inflammation of the central nervous system. Our studies have explored the positive role of activation of adenosine 2A receptors (A2ARs) in protect adult BTBR mice against autism related behavior from the early postnatal period. However, the exact mechanism underlying the protection of A2ARs has not been comprehensively investigated. Methods: The persistent protection of early postnatal activation of A2ARs in the adult BTBR mice were detected utilizing behavior tests. Pathological variation in the peripheral blood of autism patients were analyzed by transcriptomic analysis, including mroast and protein–protein interactions (PPIs). The clues were further explored and validated by real-time RT PCR, western blotting, immunohistochemistry and transcriptomic analysis in the mouse cortex. The blood brain barrier of mouse were spotted by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Results: Abnormal activation of myeloid cells, especially the neutrophil were detected in the peripheral blood of autism patients and BTBR mouse cortex. The BBB permeability of BTBR mouse were significantly increased, which might facilitated the abnormal infiltration of neutrophils spotted in the BTBR mouse cortex. Further, the early postnatal activation of A2ARs effectively revers the abnormal activation and invading of neutrophils in the mouse cortex, might result in the significantly moderation of the autism related behavior of adult BTBR mice, following decrease of the chronic inflammation in the mouse cortex during the early postnatal period. Conclusions: We found the abnormal condition of myeloid cells in the autism patients and BTBR mice, and the adding infiltration of neutrohpils in the mouse cortex. We concluded that the early activation of A2ARs could effectively decreased the autism related behavior of adult BTBR mice via reversing the abnormal activation of myeloid cells and the pathological invading of neutrophils in the mouse cortex.

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Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

The early postnatal activation of A2ARs protects BTBR mice against autism related behavior

Zhou

Yang

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Using data collected by Michael V. Lombardo et al, who recruited a total of 188 toddlers, including 81 individuals with ASD at approximately 3-4 years of age [11], we found that myeloid cells were signi cantly boosted and activated, particularly neutrophils (Fig. 2C-D), in the peripheral blood of autism patients.…”

Section: Discussionmentioning

confidence: 82%

“…ASD patients and ASD model rodents display immune dysfunction [7][8][9]. Vital pathways enriched in in ammatory regulators, such as interleukin-17A (IL-17A), interleukin-6 (IL-6) and MCP-1, are notable [9][10][11]. The expression levels of ASD risk genes coexpressed in peripheral blood leukocytes and brain tissues were proven to be associated with multivariate functional neuroimaging (fMRI) response to speech between typically developing toddlers and toddlers with ASD [12].…”

Section: Introductionmentioning

confidence: 99%

Early postnatal activation of A2ARs alleviates social deficits by attenuating the abnormal infiltration of peripheral neutrophils in the BTBR T + Itpr3 tf /J mouse model of autism

Zhou

Yang

et al. 2022

Preprint

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Background Previous studies have mainly focused on the immediate effect of drugs on autism spectrum disorders (ASDs) and complex heterogeneous neurodevelopmental disorders that have been proven to be involved with the chronic inflammation of the central nervous system. Our prior work has explored the positive role of activation of adenosine 2A receptors (A2ARs) in protecting adult BTBR T+ Itpr3tf/J mice against autism-related behaviour from the early postnatal period. However, the exact mechanism underlying the protection of A2ARs has not been comprehensively investigated. Methods The persistent protection of early postnatal activation of A2ARs in adult BTBR mice was detected utilizing behaviour tests. Pathological variation in the peripheral blood of autism patients was analysed by transcriptomic analysis, including MROAST and protein–protein interaction (PPI) analysis. The clues were further explored and validated by real-time (RT) PCR, western blotting, immunohistochemistry and transcriptomic analysis in the mouse cortex. The blood brain barrier of mice was identified by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results Abnormal activation of myeloid cells, especially neutrophils, was detected in the peripheral blood of autism patients and the BTBR mouse cortex. The BBB permeability of BTBR mice was significantly increased, which may have facilitated the abnormal infiltration of neutrophils observed in the BTBR mouse cortex. Furthermore, the early postnatal activation of A2ARs effectively reverses the abnormal activation and invasion of neutrophils in the mouse cortex and might result in the significant moderation of autism-related behaviour in adult BTBR mice, followed by a decrease in chronic inflammation in the mouse cortex during the early postnatal period. Conclusions We found abnormal myeloid cells in autism patients and BTBR mice and increased infiltration of neutrophils in the mouse cortex. We concluded that the early activation of A2ARs could effectively decrease the autism-related behaviour of adult BTBR mice by reversing the abnormal activation of myeloid cells and the pathological invasion of neutrophils in the mouse cortex.

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“…Structural and functional alterations of primary somatosensory cortex have been reported to regulate social behavior, socio-emotional processing and affective functions in humans and preclinical animal models [33][34][35][36]. To investigate the cellular mechanism underlying abnormal behaviors in Wdr62 Nex-cKO mice, we analyzed pyramidal neuronal morphology by crossing Wdr62 Nex-cKO mice with Thy1-GFPm transgenic mice, which can express EGFP in sparse subsets of excitatory neurons [37].…”

Section: Wdr62 Regulates Neuronal Dendritic Complexity and Spine Dens...mentioning

confidence: 99%

WDR62 deficiency results in synaptic dysfunction and ASD-like behaviors in mice, which can be ameliorated by RA repletion

Zhi

Liu

et al. 2022

Preprint

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Background: Brain size abnormality is correlated with increased frequency of autism spectrum disorder (ASD) in offspring. Genetic analysis indicates that many heterozygous mutations of microcephaly-associated genes including WD repeat domain 62 (WDR62), are associated with ASD; however, biological evidence is still lacking.Methods: To investigate the association between WDR62 and ASD, we generated both Wdr62 conventional knockout (Wdr62 KO) and Nex-Cre conditional knockout (Wdr62 Nex-cKO) mice. We investigated and compared the behavioral alterations between these mice and their littermate controls. Morphological and electrophysiological analyses were adopted to explore the mechanism underlying the abnormal behaviors. Furthermore, all-trans retinoic acid (RA), a derivative of vitamin A, was tried to treat aberrant behaviors.Results: Our study showed that Wdr62 KO led to reduced brain size with impaired learning and memory, as well as ASD-like behaviors in mice. Interestingly, aberrant social interactions and repetitive behaviors were also observed in Wdr62 Nex-cKO mice, but no deficits in brain size, and learning and memory. Mechanically, we found that WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. Finally, we revealed that RA gavages could significantly alleviate ASD-like behaviors in WDR62 haploinsufficiency mice probably by complementing the expression of ASD and synapse-related genes. Limitations: RA oral gavage significantly alleviated ASD-like behavior in WDR62 haploinsufficiency mice, while whether RA supplement could ameliorate ASD-like behavior in WDR62 KO mice is unknown. In addition, it is not known that whether the content of RA in Wdr62 deficiency mice is changed. Conclusions: Our findings provide not only new insight into the roles of WDR62 in brain development, but also a new perspective for the relationship between microcephaly gene WDR62 and ASD etiology which will benefit clinical diagnosis and intervention of ASD.

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MCP-1 Signaling Disrupts Social Behavior by Modulating Brain Volumetric Changes and Microglia Morphology

Cited by 22 publications

References 64 publications

The early postnatal activation of A2ARs protects BTBR mice against autism related behavior

The early postnatal activation of A2ARs protects BTBR mice against autism related behavior

Early postnatal activation of A2ARs alleviates social deficits by attenuating the abnormal infiltration of peripheral neutrophils in the BTBR T + Itpr3 tf /J mouse model of autism

WDR62 deficiency results in synaptic dysfunction and ASD-like behaviors in mice, which can be ameliorated by RA repletion

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