Ethanol impairs muscarinic receptor-induced neuritogenesis in rat hippocampal slices: Role of astrocytes and extracellular matrix proteins

Giordano, Gennaro; Guizzetti, Marina; Dao, Khoi; Mattison, Hayley A.; Costa, Lucio G.

doi:10.1016/j.bcp.2011.08.014

Cited by 24 publications

(22 citation statements)

References 57 publications

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“…This results in an increase in neurite outgrowth of hippocampal neurons in astrocyte–neuron co-cultures and hippocampal slices, an effect mediated by M3 muscarinic receptors (8, 25). …”

Section: Astrocytes In Brain Developmentmentioning

confidence: 99%

Glia and Neurodevelopment: Focus on Fetal Alcohol Spectrum Disorders

et al. 2014

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During the last 20 years, new and exciting roles for glial cells in brain development have been described. Moreover, several recent studies implicated glial cells in the pathogenesis of neurodevelopmental disorders including Down syndrome, Fragile X syndrome, Rett Syndrome, Autism Spectrum Disorders, and Fetal Alcohol Spectrum Disorders (FASD). Abnormalities in glial cell development and proliferation and increased glial cell apoptosis contribute to the adverse effects of ethanol on the developing brain and it is becoming apparent that the effects of fetal alcohol are due, at least in part, to effects on glial cells affecting their ability to modulate neuronal development and function. The three major classes of glial cells, astrocytes, oligodendrocytes, and microglia as well as their precursors are affected by ethanol during brain development. Alterations in glial cell functions by ethanol dramatically affect neuronal development, survival, and function and ultimately impair the development of the proper brain architecture and connectivity. For instance, ethanol inhibits astrocyte-mediated neuritogenesis and oligodendrocyte development, survival and myelination; furthermore, ethanol induces microglia activation and oxidative stress leading to the exacerbation of ethanol-induced neuronal cell death. This review article describes the most significant recent findings pertaining the effects of ethanol on glial cells and their significance in the pathophysiology of FASD and other neurodevelopmental disorders.

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“…This results in an increase in neurite outgrowth of hippocampal neurons in astrocyte–neuron co-cultures and hippocampal slices, an effect mediated by M3 muscarinic receptors (8, 25). …”

Section: Astrocytes In Brain Developmentmentioning

confidence: 99%

Glia and Neurodevelopment: Focus on Fetal Alcohol Spectrum Disorders

et al. 2014

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“…FN in particular plays a primary role in cell adhesion, cell migration, and neurite outgrowth (Kiryushko et al, 2004; Matthiessen et al, 1989; Tom et al, 2004). Highlighting its role in neuronal development, inhibition of FN by function-blocking antibodies strongly inhibits neurite outgrowth, as shown in primary neurons (Guizzetti et al, 2008), as well as in hippocampal slices (Giordano et al, 2011). In the present study we showed that DZ and DZO decrease intracellular and extracellular-bound protein levels of FN in astrocytes.…”

Section: Discussionmentioning

confidence: 95%

“…Astrocytes are increasingly recognized as important contributors to central nervous system function and development. In addition to playing important roles in maintaining ion homeostasis, forming the blood brain barrier, and regulating glutamate recycling from the synapse (He and Sun, 2007; Nedergaard et al, 2003), astrocytes have more recently been shown to have integral roles in neuronal differentiation, including neuritogenesis (Giordano et al, 2011; Guizzetti et al, 2008; 2010) and synaptogenesis (Christopherson et al, 2005). Our laboratory has previously shown that certain chemicals, including manganese and ethanol, can affect astrocyte functions and indirectly inhibit neurite outgrowth (Giordano et al, 2009; Guizzetti et al, 2010; VanDeMark et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Diazinon and diazoxon impair the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons

Pizzurro

Dao

Costa

2014

Toxicology and Applied Pharmacology

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Evidence from in vivo and epidemiological studies suggests that organophosphorus insecticides (OPs) are developmental neurotoxicants, but possible underlying mechanisms are still unclear. Astrocytes are increasingly recognized for their active role in normal neuronal development. This study sought to investigate whether the widely-used OP diazinon (DZ), and its oxygen metabolite diazoxon (DZO), would affect glial-neuronal interactions as a potential mechanism of developmental neurotoxicity. Specifically, we investigated the effects of DZ and DZO on the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons. The results show that both DZ and DZO adversely affect astrocyte function, resulting in inhibited neurite outgrowth in hippocampal neurons. This effect appears to be mediated by oxidative stress, as indicated by OP-induced increased reactive oxygen species production in astrocytes and prevention of neurite outgrowth inhibition by antioxidants. The concentrations of OPs were devoid of cytotoxicity, and cause limited acetylcholinesterase inhibition in astrocytes (18 and 25% for DZ and DZO, respectively). Among astrocytic neuritogenic factors, a most important one is the extracellular matrix protein fibronectin. DZ and DZO decreased levels of fibronectin in astrocytes, and this effect was also attenuated by antioxidants. Underscoring the importance of fibronectin in this context, adding exogenous fibronectin to the co-culture system successfully prevented inhibition of neurite outgrowth caused by DZ and DZO. These results indicate that DZ and DZO increase oxidative stress in astrocytes, and this in turn modulates astrocytic fibronectin, leading to impaired neurite outgrowth in hippocampal neurons.

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“…On the other hand, MeCP2 has been shown to either increase or decrease the neurite morphology. Neuronal morphology is also influenced by nearby glial cells (Giordano et al, 2011). The absence of MeCP2 in adjacent glial cells has also been shown to be influencing the neuronal morphology (Ballas et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Ethanol deregulates Mecp2/MeCP2 in differentiating neural stem cells via interplay between 5-methylcytosine and 5-hydroxymethylcytosine at the Mecp2 regulatory elements

Liyanage

Zachariah

Davie

et al. 2015

Experimental Neurology

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Methyl CpG Binding Protein 2 (MeCP2) is an important epigenetic factor in the brain. MeCP2 expression is affected by different environmental insults including alcohol exposure. Accumulating evidence supports the role of aberrant MeCP2 expression in ethanol exposureinduced neurological symptoms. However, the underlying molecular mechanisms of ethanolinduced MeCP2 deregulation remain elusive. To study the effect of ethanol on Mecp2/MeCP2 expression during neurodifferentiation, we established an in vitro model of ethanol exposure, using differentiating embryonic brain-derived neural stem cells (NSC). Previously, we demonstrated the impact of DNA methylation at the Mecp2 regulatory elements (REs) on Mecp2/ MeCP2 expression in vitro and in vivo. Here, we studied whether altered DNA methylation at these REs is associated with the Mecp2/MeCP2 misexpression induced by ethanol. Binge-like and continuous ethanol exposure upregulated Mecp2/MeCP2, while ethanol withdrawal downregulated its expression. DNA methylation analysis by methylated DNA immunoprecipitation indicated that increased 5-hydroxymethylcytosine (5hmC) and decreased 5-methylcytosine (5mC) enrichment at specific REs were associated with upregulated Mecp2/MeCP2 following continuous ethanol exposure. The reduced Mecp2/MeCP2 expression upon ethanol withdrawal was associated with reduced 5hmC and increased 5mC enrichment at these REs. Moreover, ethanol altered global DNA methylation (5mC and 5hmC). Under the tested conditions, ethanol had minimal effects on Authors' contributionsVichithra R.B. Liyanage: Conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. Robby M. Zachariah: Conception and design, collection and assembly of data, and final approval of manuscript. James R. Davie: Scientific input, manuscript revisions, and final approval of manuscript. Mojgan Rastegar: Conception and design, contributed reagents/materials/analysis tools, data analysis and interpretation, manuscript writing, and final approval of manuscript. Conflict of interest statement

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Ethanol impairs muscarinic receptor-induced neuritogenesis in rat hippocampal slices: Role of astrocytes and extracellular matrix proteins

Cited by 24 publications

References 57 publications

Glia and Neurodevelopment: Focus on Fetal Alcohol Spectrum Disorders

Glia and Neurodevelopment: Focus on Fetal Alcohol Spectrum Disorders

Diazinon and diazoxon impair the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons

Ethanol deregulates Mecp2/MeCP2 in differentiating neural stem cells via interplay between 5-methylcytosine and 5-hydroxymethylcytosine at the Mecp2 regulatory elements

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