Placental endocrine function shapes cerebellar development and social behavior

Vacher, Claire-Marie; Lacaille, Hélène; O'Reilly, Jiaqi J.; Salzbank, Jacquelyn; Bakalar, Dana; Sebaoui, Sonia; Lière, Philippe; Clarkson-Paredes, Cheryl; Sasaki, Toru; Sathyanesan, A. G.; Kratimenos, Panagiotis; Ellegood, Jacob; Lerch, Jason P.; Imamura, Yuka; Popratiloff, Anastas; Hashimoto-Torii, Kazue; Gallo, Vittorio; Schumacher, Michaël; Penn, Anna A.

doi:10.1038/s41593-021-00896-4

Cited by 61 publications

(73 citation statements)

References 77 publications

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“…However, the number of BA10 GABAproducing cells was decreased in preterm male infants, which is consistent with our former study (Lacaille et al, 2019) as well as other studies of preterm birth brain (Robinson et al, 2006;Panda et al, 2018) and psychiatric disorders (Hashimoto et al, 2008;Mellios et al, 2009;Hashemi et al, 2017). Pharmacological effects of neuroprotective agents such as the GABA agonist and anti-inflammatory compound allopregnanolone are being investigated in the context of preterm birth and show promising results (Vacher et al, 2021). New cellular models have been developed and will give the opportunity to investigate the environmental and genetic factors underlying injury in the developing human brain (Paşca et al, 2019).…”

Section: Discussionsupporting

confidence: 91%

Preterm Birth Alters the Maturation of the GABAergic System in the Human Prefrontal Cortex

Lacaille

Vacher

Penn

2022

Front. Mol. Neurosci.

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Developmental changes in GABAergic and glutamatergic systems during frontal lobe development have been hypothesized to play a key role in neurodevelopmental disorders seen in children born very preterm or at/with low birth weight, but the associated cellular changes have not yet been identified. Here we studied the molecular development of the GABAergic system specifically in the dorsolateral prefrontal cortex, a region that has been implicated in neurodevelopmental and psychiatric disorders. The maturation state of the GABAergic system in this region was assessed in human post-mortem brain samples, from term infants ranging in age from 0 to 8 months (n = 17 male, 9 female). Gene expression was measured for 47 GABAergic genes and used to calculate a maturation index. This maturation index was significantly more dynamic in male than female infants. To evaluate the impact of premature birth on the GABAergic system development, samples from 1-month-old term (n = 9 male, 4 female) and 1-month corrected-age very preterm (n = 8 male, 6 female) infants, were compared using the same gene list and methodology. The maturation index for the GABAergic system was significantly lower (−50%, p < 0.05) in male preterm infants, with major alterations in genes linked to GABAergic function in astrocytes, suggesting astrocytic GABAergic developmental changes as a new cellular mechanism underlying preterm brain injury.

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Section: Discussionsupporting

confidence: 91%

Preterm Birth Alters the Maturation of the GABAergic System in the Human Prefrontal Cortex

Lacaille

Vacher

Penn

2022

Front. Mol. Neurosci.

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“…Similar results were found in human preterm infants that were characterized by premature loss of the placenta ( 59 ). This study suggests that GABA A receptor function in female mice might not be disrupted by low ALLO levels or that female mice may recruit a compensatory mechanism in response to impairments in GABA A receptor function ( 59 ). Sex bias in ASD may be related to chromosomal and hormonal mechanisms, immune activation, or interactions among sex, genetics, and environmental factors ( 60 ).…”

Section: Discussionsupporting

confidence: 84%

“…A recent study reported that low placenta levels of allopregnanolone (ALLO), a progesterone-derived GABA A receptor modulator, resulted in sex-dependent alterations of neurodevelopment and behavior in offspring ( 59 ). Male plKO mice that were derived from pregnant plKO mice that have specific placental ALLO reduction exhibited ASD-like behaviors, including social deficits, and an increase in cerebellar myelin proteins on P30, whereas female plKO mice did not exhibit these changes ( 59 ). Similar results were found in human preterm infants that were characterized by premature loss of the placenta ( 59 ).…”

Section: Discussionmentioning

confidence: 99%

“…Male plKO mice that were derived from pregnant plKO mice that have specific placental ALLO reduction exhibited ASD-like behaviors, including social deficits, and an increase in cerebellar myelin proteins on P30, whereas female plKO mice did not exhibit these changes ( 59 ). Similar results were found in human preterm infants that were characterized by premature loss of the placenta ( 59 ). This study suggests that GABA A receptor function in female mice might not be disrupted by low ALLO levels or that female mice may recruit a compensatory mechanism in response to impairments in GABA A receptor function ( 59 ).…”

Section: Discussionmentioning

confidence: 99%

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Exposure to GABAA Receptor Antagonist Picrotoxin in Pregnant Mice Causes Autism-Like Behaviors and Aberrant Gene Expression in Offspring

et al. 2022

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by impairments in social interaction and restricted/repetitive behaviors. The neurotransmitter γ-aminobutyric acid (GABA) through GABAA receptor signaling in the immature brain plays a key role in the development of neuronal circuits. Excitatory/inhibitory imbalance in the mature brain has been investigated as a pathophysiological mechanism of ASD. However, whether and how disturbances of GABA signaling in embryos that are caused by GABAA receptor inhibitors cause ASD-like pathophysiology are poorly understood. The present study examined whether exposure to the GABAA receptor antagonist picrotoxin causes ASD-like pathophysiology in offspring by conducting behavioral tests from the juvenile period to adulthood and performing gene expression analyses in mature mouse brains. Here, we found that male mice that were prenatally exposed to picrotoxin exhibited a reduction of active interaction time in the social interaction test in both adolescence and adulthood. The gene expression analyses showed that picrotoxin-exposed male mice exhibited a significant increase in the gene expression of odorant receptors. Weighted gene co-expression network analysis showed a strong correlation between social interaction and enrichment of the “odorant binding” pathway gene module. Our findings suggest that exposure to a GABAA receptor inhibitor during the embryonic period induces ASD-like behavior, and impairments in odorant function may contribute to social deficits in offspring.

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“…The mechanisms underlying the association between ASD candidate genes and the neurobiology of autism are complex because genes encode multiple highly complex functions in different regions of the brain. To date, numerous studies have demonstrated associations between brain abnormalities and ASD (Maynard et al, 2021 ; Vacher et al, 2021 ; Rubin, 2022 ). Furthermore, studies have increasingly highlighted the cerebellum as a pathological area of the brain in ASD (Carta et al, 2019 ; Sathyanesan et al, 2019 ; Kelly et al, 2020 ; Vacher et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder

Wang

et al. 2022

Front. Neuroinform.

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, characterized by marked genetic heterogeneity. In this study, two independent microarray datasets of cerebellum of ASD were integrative analyzed by NetworkAnalyst to screen candidate crucial genes. NetworkAnalyst identified two up-regulated genes, Jun proto-oncogene (JUN) and platelet derived growth factor receptor alpha (PDGFRA), as the most crucial genes in cerebellum of ASD patients. Based on KEGG pathway database, genes associated with JUN in the cerebellum highlight the pathways of Th17 cell differentiation and Th1 and Th2 cell differentiation. Genes associated with PDGFRA in the cerebellum were found enriched in pathways in EGFR tyrosine kinase inhibitor resistance and Rap1 signaling pathway. Analyzing all differentially expressed genes (DEGs) from the two datasets, Gene Set Enrichment Analysis (GSEA) brought out IL17 signaling pathway, which is related to the expression of JUN and PDGFRA. The ImmuCellAI found the elevated expression of JUN and PDGFRA correlating with increased Th17 and monocytes suggests JUN and PDGFRA may regulate Th17 cell activation and monocytes infiltrating. Mice model of maternal immune activation demonstrated that JUN and PDGFRA are up-regulated and related to the ASD-like behaviors that provide insights into the molecular mechanisms underlying the altered IL17 signaling pathway in ASD and may enable novel therapeutic strategies.

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Placental endocrine function shapes cerebellar development and social behavior

Cited by 61 publications

References 77 publications

Preterm Birth Alters the Maturation of the GABAergic System in the Human Prefrontal Cortex

Preterm Birth Alters the Maturation of the GABAergic System in the Human Prefrontal Cortex

Exposure to GABAA Receptor Antagonist Picrotoxin in Pregnant Mice Causes Autism-Like Behaviors and Aberrant Gene Expression in Offspring

JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder

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