AhR Deletion Promotes Aberrant Morphogenesis and Synaptic Activity of Adult-Generated Granule Neurons and Impairs Hippocampus-Dependent Memory

Parra, Juana González; Cuartero, María Isabel; Pérez-Ruíz, Alberto; García‐Culebras, Alicia; Martín, Ricardo; Sánchez‐Prieto, José; García‐Segura, Juan M.; Lizasoaín, Ignacio; Moro, Marı́a A.

doi:10.1523/eneuro.0370-17.2018

Cited by 30 publications

(20 citation statements)

References 65 publications

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“…Low AHR signaling triggered restorative ependymoglial proliferation after acute injury, while high AHR signaling promoted ependymoglial differentiation toward post-mitotic neurons after injury [45]. Also, another study reported that tamoxifen-inducible Nestin-Cre AHR deletion after postnatal day 30 increased adult hippocampal neurogenesis in nonstroke mice [46], which is in line with our findings that AHR plays a role in regulation of adult neurogenesis. However, the function of adult-born neurons after stroke remains unknown.…”

Section: Discussionsupporting

confidence: 91%

Aryl hydrocarbon receptor modulates stroke-induced astrogliosis and neurogenesis in the adult mouse brain

Chen¹,

Chang

Huang

et al. 2019

J Neuroinflammation

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Background: The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor activated by environmental agonists and dietary tryptophan metabolites for the immune response and cell cycle regulation. Emerging evidence suggests that AHR activation after acute stroke may play a role in brain ischemic injury. However, whether AHR activation alters poststroke astrogliosis and neurogenesis remains unknown. Methods: We adopted conditional knockout of AHR from nestin-expressing neural stem/progenitor cells (AHRcKO) and wild-type (WT) mice in the permanent middle cerebral artery occlusion (MCAO) model. WT mice were treated with either vehicle or the AHR antagonist 6,2′,4′-trimethoxyflavone (TMF, 5 mg/kg/day) intraperitoneally. The animals were examined at 2 and 7 days after MCAO. Results: The AHR signaling pathway was significantly upregulated after stroke. Both TMF-treated WT and AHRcKO mice showed significantly decreased infarct volume, improved sensorimotor, and nonspatial working memory functions compared with their respective controls. AHR immunoreactivities were increased predominantly in activated microglia and astrocytes after MCAO compared with the normal WT controls. The TMF-treated WT and AHRcKO mice demonstrated significant amelioration of astrogliosis and microgliosis. Interestingly, these mice also showed augmentation of neural progenitor cell proliferation at the ipsilesional neurogenic subventricular zone (SVZ) and the hippocampal subgranular zone. At the peri-infarct cortex, the ipsilesional SVZ/striatum, and the hippocampus, both the TMF-treated and AHRcKO mice demonstrated downregulated IL-1β, IL-6, IFN-γ, CXCL1, and S100β, and concomitantly upregulated Neurogenin 2 and Neurogenin 1. Conclusion: Neural cell-specific AHR activation following acute ischemic stroke increased astrogliosis and suppressed neurogenesis in adult mice. AHR inhibition in acute stroke may potentially benefit functional outcomes likely through reducing proinflammatory gliosis and preserving neurogenesis.

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Section: Discussionsupporting

confidence: 91%

Aryl hydrocarbon receptor modulates stroke-induced astrogliosis and neurogenesis in the adult mouse brain

Chen¹,

Chang

Huang

et al. 2019

J Neuroinflammation

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“…Granule cells of the dentate gyrus in Ahr −= − mice show a similar morphological phenotype to the phenotype we observed in TCDD-exposed mice, namely higher arborization in proximal apical dendrites and a shorter apical length (de la Parra et al 2018). This similarity could suggest that TCDD exposure disrupts the physiological role of AHR, resulting in similar phenotypes in loss of AHR and TCDD exposure models.…”

Section: Brain Morphology Outcomes Of Gestational Low-dose Tcdd Exposuresupporting

confidence: 77%

Effects of Low-Dose Gestational TCDD Exposure on Behavior and on Hippocampal Neuron Morphology and Gene Expression in Mice

Gileadi

Swamy

Hore

et al. 2021

Environ Health Perspect

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BACKGROUND: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans. OBJECTIVES: The aim of the study was to establish a dietary low-dose gestational TCDD exposure protocol and performed an initial characterization of the effects on offspring behavior, neurodevelopmental phenotypes, and gene expression. METHODS: Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD (9 ng TCDD/kg body weight per day) or a control diet. The offspring were tested in a battery of behavioral tests, and structural brain alterations were investigated by magnetic resonance imaging. The dendritic morphology of pyramidal neurons in the hippocampal Cornu Ammonis (CA)1 area was analyzed. RNA sequencing was performed on hippocampi of postnatal day 14 TCDD-exposed and control offspring. RESULTS: TCDD-exposed females displayed subtle deficits in motor coordination and reversal learning. Volumetric difference between diet groups were observed in regions of the hippocampal formation, mammillary bodies, and cerebellum, alongside higher dendritic arborization of pyramidal neurons in the hippocampal CA1 region of TCDD-exposed females. RNA-seq analysis identified 405 differentially expressed genes in the hippocampus, enriched for genes with functions in regulation of microtubules, axon guidance, extracellular matrix, and genes regulated by SMAD3. DISCUSSION: Exposure to 9 ng TCDD/kg body weight per day throughout gestation was sufficient to cause specific behavioral and structural brain phenotypes in offspring. Our data suggest that alterations in SMAD3-regulated microtubule polymerization in the developing postnatal hippocampus may lead to an abnormal morphology of neuronal dendrites that persists into adulthood. These findings show that environmental low-dose gestational exposure to TCDD can have significant, long-term impacts on brain development and function.

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“…AHR expression has also been detected in the spinal cord, as reported in the Human Protein Atlas [69]. The significance of Ahr in CNS glial and neuronal cells has been further illustrated by the phenotype of mice lacking functional AHR protein, impacting neurogenesis [70][71][72].…”

Section: Ahr Expression In the Central Nervous System (Cns)mentioning

confidence: 76%

The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases

Choudhary

Malek

2020

IJMS

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which senses environmental, dietary or metabolic signals to mount a transcriptional response, vital in health and disease. As environmental stimuli and metabolic products have been shown to impact the central nervous system (CNS), a burgeoning area of research has been on the role of the AHR in ocular and non-ocular neurodegenerative diseases. Herein, we summarize our current knowledge, of AHR-controlled cellular processes and their impact on regulating pathobiology of select ocular and neurodegenerative diseases. We catalogue animal models generated to study the role of the AHR in tissue homeostasis and disease pathogenesis. Finally, we discuss the potential of targeting the AHR pathway as a therapeutic strategy, in the context of the maladies of the eye and brain.

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AhR Deletion Promotes Aberrant Morphogenesis and Synaptic Activity of Adult-Generated Granule Neurons and Impairs Hippocampus-Dependent Memory

Abstract: Visual Abstract

Cited by 30 publications

References 65 publications

Aryl hydrocarbon receptor modulates stroke-induced astrogliosis and neurogenesis in the adult mouse brain

Aryl hydrocarbon receptor modulates stroke-induced astrogliosis and neurogenesis in the adult mouse brain

Effects of Low-Dose Gestational TCDD Exposure on Behavior and on Hippocampal Neuron Morphology and Gene Expression in Mice

The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases

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