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Systematic Analysis of Environmental Chemicals That Dysregulate Critical Period Plasticity-Related Gene Expression Reveals Common Pathways That Mimic Immune Response to Pathogen.

ABSTRACT: The tens of thousands of industrial and synthetic chemicals released into the environment have an unknown but potentially significant capacity to interfere with neurodevelopment. Consequently, there is an urgent need for systematic approaches that can identify disruptive chemicals. Little is known about the impact of environmental chemicals on critical periods of developmental neuroplasticity, in large part, due to the challenge of screening thousands of chemicals. Using an integrative bioinformatics approach, we systematically scanned 2001 environmental chemicals and identified 50 chemicals that consistently dysregulate two transcriptional signatures of critical period plasticity. These chemicals included pesticides (e.g., pyridaben), antimicrobials (e.g., bacitracin), metals (e.g., mercury), anesthetics (e.g., halothane), and other chemicals and mixtures (e.g., vehicle emissions). Application of a chemogenomic enrichment analysis and hierarchical clustering across these diverse chemicals identified two clusters of chemicals with one that mimicked an immune response to pathogen, implicating inflammatory pathways and microglia as a common chemically induced neuropathological process. Thus, we established an integrative bioinformatics approach to systematically scan thousands of environmental chemicals for their ability to dysregulate molecular signatures relevant to critical periods of development.

SUBMITTER: Smith MR

PROVIDER: S-EPMC7222500 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Systematic Analysis of Environmental Chemicals That Dysregulate Critical Period Plasticity-Related Gene Expression Reveals Common Pathways That Mimic Immune Response to Pathogen.

Smith Milo R MR Yevoo Priscilla P Sadahiro Masato M Readhead Ben B Kidd Brian B Dudley Joel T JT Morishita Hirofumi H

Neural plasticity 20200505

The tens of thousands of industrial and synthetic chemicals released into the environment have an unknown but potentially significant capacity to interfere with neurodevelopment. Consequently, there is an urgent need for systematic approaches that can identify disruptive chemicals. Little is known about the impact of environmental chemicals on critical periods of developmental neuroplasticity, in large part, due to the challenge of screening thousands of chemicals. Using an integrative bioinform ...[more]

PMID: 32454811

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Project description:Critical periods are postnatal, restricted time windows of heightened plasticity in cortical neural networks, during which experience refines principal neuron wiring configurations. Here, we propose a model with two distinct types of synapses, innate synapses that establish rudimentary networks with innate function, and gestalt synapses that govern the experience-dependent refinement process. Nascent gestalt synapses are constantly formed as AMPA receptor-silent synapses which are the substrates for critical period plasticity. Experience drives the unsilencing and stabilization of gestalt synapses, as well as synapse pruning. This maturation process changes synapse patterning and consequently the functional architecture of cortical excitatory networks. Ocular dominance plasticity (ODP) in the primary visual cortex (V1) is an established experimental model for cortical plasticity. While converging evidence indicates that the start of the critical period for ODP is marked by the maturation of local inhibitory circuits, recent results support our model that critical periods end through the progressive maturation of gestalt synapses. The cooperative yet opposing function of two postsynaptic signaling scaffolds of excitatory synapses, PSD-93 and PSD-95, governs the maturation of gestalt synapses. Without those proteins, networks do not progress far beyond their innate functionality, resulting in rather impaired perception. While cortical networks remain malleable throughout life, the cellular mechanisms and the scope of critical period and adult plasticity differ. Critical period ODP is initiated with the depression of deprived eye responses in V1, whereas adult ODP is characterized by an initial increase in non-deprived eye responses. Our model proposes the gestalt synapse-based mechanism for critical period ODP, and also predicts a different mechanism for adult ODP based on the sparsity of nascent gestalt synapses at that age. Under our model, early life experience shapes the boundaries (the gestalt) for network function, both for its optimal performance as well as for its pathological state. Thus, reintroducing nascent gestalt synapses as plasticity substrates into adults may improve the network gestalt to facilitate functional recovery.

Dataset Information

Systematic Analysis of Environmental Chemicals That Dysregulate Critical Period Plasticity-Related Gene Expression Reveals Common Pathways That Mimic Immune Response to Pathogen.

Publications

Systematic Analysis of Environmental Chemicals That Dysregulate Critical Period Plasticity-Related Gene Expression Reveals Common Pathways That Mimic Immune Response to Pathogen.

Similar Datasets

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