Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

Introduction. In March 2020, the World Health Organization (WHO) announced the emergence of a global pandemic, COVID-19. A disease triggered by the new coronavirus infection (SARS-CoV-2). More recent findings indicate that the gestational period makes the mother and her offspring more susceptible to the new coronavirus and the rapid progression to the critical stage of the disease. The maternal organism presents a certain degree of immunological and cardiorespiratory deficiency due to physiological adaptations to the gestational period and, consequently, if affected by prenatal infections caused by viruses, they lead to an exacerbated Maternal Immune Activation (MIA), thus contributing to alterations in maternal-fetal neurogenesis, fetal myelinization, and is directly involved in the pathogenesis of neurodevelopmental disorders in the offspring, especially autism. Objective. This study hypothesizes that maternal COVID-19 infections during pregnancy are a potential risk for the offspring to develop Autism Spectrum Disorder. Conclusion. The exposure to viral infectious agents during the gestational period leads to exacerbated maternal immune activation. It contributes to alterations in maternal-fetal neurogenesis and is directly involved in the pathogenesis of neurodevelopmental disorders, being correlated to the predisposition to affective and psychiatric disorders in the offspring. Therefore, greater attention should be given to the offspring of pregnant women infected by COVID-19, since prenatal infectious processes have a strong correlation with the prevalence of Autistic Spectrum Disorder in the offspring.

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Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802179115 ◽

2018 ◽

Vol 115 (25) ◽

pp. E5815-E5823 ◽

Cited By ~ 57

Author(s):

Qian Ren ◽

Min Ma ◽

Jun Yang ◽

Risa Nonaka ◽

Akihiro Yamaguchi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorders ◽

Epoxide Hydrolase ◽

Neurodegenerative Disorder ◽

Lewy Bodies ◽

Soluble Epoxide Hydrolase ◽

Postmortem Brain ◽

Control Treatment ◽

Increased Activity

Parkinson’s disease (PD) is characterized as a chronic and progressive neurodegenerative disorder, and the deposition of specific protein aggregates of α-synuclein, termed Lewy bodies, is evident in multiple brain regions of PD patients. Although there are several available medications to treat PD symptoms, these medications do not prevent the progression of the disease. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with the pathogenesis of PD. Here we found that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neurotoxicity in the mouse striatum was attenuated by subsequent repeated administration of TPPU, a potent sEH inhibitor. Furthermore, deletion of the sEH gene protected against MPTP-induced neurotoxicity, while overexpression of sEH in the striatum significantly enhanced MPTP-induced neurotoxicity. Moreover, the expression of the sEH protein in the striatum from MPTP-treated mice or postmortem brain samples from patients with dementia of Lewy bodies (DLB) was significantly higher compared with control groups. Interestingly, there was a positive correlation between sEH expression and phosphorylation of α-synuclein in the striatum. Oxylipin analysis showed decreased levels of 8,9-epoxy-5Z,11Z,14Z-eicosatrienoic acid in the striatum of MPTP-treated mice, suggesting increased activity of sEH in this region. Interestingly, the expression of sEH mRNA in human PARK2 iPSC-derived neurons was higher than that of healthy control. Treatment with TPPU protected against apoptosis in human PARK2 iPSC-derived dopaminergic neurons. These findings suggest that increased activity of sEH in the striatum plays a key role in the pathogenesis of neurodegenerative disorders such as PD and DLB. Therefore, sEH may represent a promising therapeutic target for α-synuclein–related neurodegenerative disorders.

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Investigating the Effect of Reduced Serotonin Transporter Expression in a Maternal Immune Activation Model of Neurodevelopmental Disorders

10.26686/wgtn.16613965 ◽

2021 ◽

Author(s):

◽

Alexandra Lister

Keyword(s):

Serotonin Transporter ◽

Immune Activation ◽

Neurodevelopmental Disorders ◽

Allelic Variation ◽

Autism Spectrum ◽

Poly I:C ◽

Supporting Evidence ◽

Maternal Immune Activation ◽

Behavioural Effects ◽

The Impact

<p>Maternal Immune Activation (MIA) during early pregnancy is an established risk factor for the occurrence of neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) and schizophrenia (SCZ) in offspring. Serotonin signalling is also implicated in both ASD and SCZ, in conjunction with a known and extensive influence in neural development. Using a Wistar serotonin transporter (SERT) knockout model to mimic allelic variation in the human serotonin transporter promoter (5‐HTTLPR), this research investigates the impact of full or reduced SERT function on the effect of poly I:C-induced MIA in offspring. Experimental design focuses on ultrasonic vocalisation communication in postnatal day (PND) 7 offspring, followed by genetic expression of the Rac1/Kal7/Disc1 signalosome pathway at PND21 previously implicated in SCZ pathology. Results from behavioural analysis of pups indicate a statistically significant increase in calling and call complexity in pups heterozygous for the SERT (SERT HET) compared to wildtype (WT). When separated by sex, this trend remains consistent however only reaches significance in male offspring. Male SERT HET pups also a significant treatment effect in call complexity, and a significant genotype/treatment interaction which suggests an increased susceptibility to MIA-induced behavioural effects. Additionally, poly I:C exposed pups show increased expression of Disc1, supporting evidence that this pathway may be affected in neurodevelopmental disorders. No genotype and sex effects were observed in signalosome expression; however, this study may be too underpowered to detect these effects. These results suggest that differences between sex and SERT genotype in offspring may modulate the behavioural effects of MIA in rodent models of NDD, with more study required to assess these differences in a molecular context. Furthermore, this study aims to address the overall inconsistency and misrepresentation of statistical methods in MIA models by employing MIA validation tests and linear mixed modelling to account for litter variation. In summary, the research presented in this thesis reports initial evidence suggesting SERT genotype may influence the effect of MIA, however further research is necessary to characterise the effect of genotype on MIA challenge during gestation.</p>

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Investigating the Effect of Reduced Serotonin Transporter Expression in a Maternal Immune Activation Model of Neurodevelopmental Disorders

10.26686/wgtn.16613965.v1 ◽

2021 ◽

Author(s):

◽

Alexandra Lister

Keyword(s):

Serotonin Transporter ◽

Immune Activation ◽

Neurodevelopmental Disorders ◽

Allelic Variation ◽

Autism Spectrum ◽

Poly I:C ◽

Supporting Evidence ◽

Maternal Immune Activation ◽

Behavioural Effects ◽

The Impact

<p>Maternal Immune Activation (MIA) during early pregnancy is an established risk factor for the occurrence of neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) and schizophrenia (SCZ) in offspring. Serotonin signalling is also implicated in both ASD and SCZ, in conjunction with a known and extensive influence in neural development. Using a Wistar serotonin transporter (SERT) knockout model to mimic allelic variation in the human serotonin transporter promoter (5‐HTTLPR), this research investigates the impact of full or reduced SERT function on the effect of poly I:C-induced MIA in offspring. Experimental design focuses on ultrasonic vocalisation communication in postnatal day (PND) 7 offspring, followed by genetic expression of the Rac1/Kal7/Disc1 signalosome pathway at PND21 previously implicated in SCZ pathology. Results from behavioural analysis of pups indicate a statistically significant increase in calling and call complexity in pups heterozygous for the SERT (SERT HET) compared to wildtype (WT). When separated by sex, this trend remains consistent however only reaches significance in male offspring. Male SERT HET pups also a significant treatment effect in call complexity, and a significant genotype/treatment interaction which suggests an increased susceptibility to MIA-induced behavioural effects. Additionally, poly I:C exposed pups show increased expression of Disc1, supporting evidence that this pathway may be affected in neurodevelopmental disorders. No genotype and sex effects were observed in signalosome expression; however, this study may be too underpowered to detect these effects. These results suggest that differences between sex and SERT genotype in offspring may modulate the behavioural effects of MIA in rodent models of NDD, with more study required to assess these differences in a molecular context. Furthermore, this study aims to address the overall inconsistency and misrepresentation of statistical methods in MIA models by employing MIA validation tests and linear mixed modelling to account for litter variation. In summary, the research presented in this thesis reports initial evidence suggesting SERT genotype may influence the effect of MIA, however further research is necessary to characterise the effect of genotype on MIA challenge during gestation.</p>

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Maternal glyphosate exposure causes autism-like behaviors in offspring through increased expression of soluble epoxide hydrolase

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1922287117 ◽

2020 ◽

Vol 117 (21) ◽

pp. 11753-11759 ◽

Cited By ~ 12

Author(s):

Yaoyu Pu ◽

Jun Yang ◽

Lijia Chang ◽

Youge Qu ◽

Siming Wang ◽

...

Keyword(s):

Fatty Acids ◽

Gut Microbiota ◽

Epoxide Hydrolase ◽

Short Chain Fatty Acids ◽

Soluble Epoxide Hydrolase ◽

Epidemiological Studies ◽

Autism Spectrum ◽

Maternal Exposure ◽

Behavioral Abnormalities ◽

Increased Activity

Epidemiological studies suggest that exposure to herbicides during pregnancy might increase risk for autism spectrum disorder (ASD) in offspring. However, the precise mechanisms underlying the risk of ASD by herbicides such as glyphosate remain unclear. Soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids is shown to play a key role in the development of ASD in offspring after maternal immune activation. Here, we found ASD-like behavioral abnormalities in juvenile offspring after maternal exposure to high levels of formulated glyphosate. Furthermore, we found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring, and oxylipin analysis showed decreased levels of epoxy-fatty acids such as 8 (9)-EpETrE in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure, supporting increased activity of sEH in the offspring. Moreover, we found abnormal composition of gut microbiota and short-chain fatty acids in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU (an sEH inhibitor) to pregnant mothers from E5 to P21 prevented ASD-like behaviors such as social interaction deficits and increased grooming time in the juvenile offspring after maternal glyphosate exposure. These findings suggest that maternal exposure to high levels of glyphosate causes ASD-like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH might play a role in ASD-like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH may represent a target for ASD in offspring after maternal stress from occupational exposure to contaminants.

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Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1601532113 ◽

2016 ◽

Vol 113 (13) ◽

pp. E1944-E1952 ◽

Cited By ~ 80

Author(s):

Qian Ren ◽

Min Ma ◽

Tamaki Ishima ◽

Christophe Morisseau ◽

Jun Yang ◽

...

Keyword(s):

Prefrontal Cortex ◽

Epoxide Hydrolase ◽

Social Defeat ◽

Soluble Epoxide Hydrolase ◽

Postmortem Brain ◽

Psychiatric Disease ◽

Psychiatric Diseases ◽

Social Defeat Stress ◽

Stress Resilience ◽

Beneficial Effects

Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depression-like behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.

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The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats

Brain Sciences ◽

10.3390/brainsci11030344 ◽

2021 ◽

Vol 11 (3) ◽

pp. 344

Author(s):

Kinga Gzielo ◽

Agnieszka Potasiewicz ◽

Ewa Litwa ◽

Diana Piotrowska ◽

Piotr Popik ◽

...

Keyword(s):

Immune Activation ◽

Social Play ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Male Rats ◽

Poly I:C ◽

Maternal Immune Activation ◽

Increased Risk ◽

Adolescent Rats ◽

The Impact

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

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