Integrative Analysis of Disease Signatures Shows Inflammation Disrupts Juvenile Experience-Dependent Cortical Plasticity

Smith, Mary Patricia; Burman, Poromendro; Sadahiro, Masato; Kidd, Brian; Dudley, Joel T.; Morishita, Hirofumi

doi:10.1523/eneuro.0240-16.2016

Cited by 18 publications

(31 citation statements)

References 70 publications

(85 reference statements)

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“…We used Limma [28] to quantile normalized raw microrray probe-level data and RankProd [29] to compute rank-based differential expression of mouse genes, which we mapped to orthologous human genes using the Mouse Genome Informatics homology reference to yield 176 and 98 gene signatures (juvenile wild-type and adult Lynx1 −/− respectively), 35 of which were shared (Fisher Exact Test: OR=37.1, 95% CI = 23.8–58.0, p < 2.2 ×10 −16 , replication of comparison found in [14]) (Figure 1a). Both juvenile and Lynx1 −/− mice have elevated experience-dependent plasticity, whereas adult wild-type mice have reduced plasticity.…”

Section: Methodssupporting

confidence: 52%

“…Lynx1 −/− mice have elevated, juvenile-like plasticity [15] and were used to control for non-plasticity aspects of the juvenile signature. We defined putative plasticity genes as the 35 shared between the two signatures (Fisher Exact Test: OR=37.1, 95% CI = 23.8–58.0, p < 2.2 ×10 −16 , this statistic reproduced as in [14]). Interestingly, using gene set enrichment we found that these genes are predominantly enriched for immune processes, including gene sets related to neutrophil degranulation, defense response to fungus, immune cell chemotaxis, apoptotic pathways, and cytokine production (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…These genes are correlated to experience-dependent neural plasticity across two mouse models, suggesting that LOF in human may confer risk for neurodevelopmental disorders by disrupting plasticity. Moreover, these genes are regulated by inflammation via lipopolysaccharide, which also disrupts experience-dependent plasticity in juvenile mouse [14], suggesting LOF in these genes may disrupt a component of neural-immune interaction to confer risk for human neurodevelopment. Consistent with that perspective, schizophrenia and epilepsy have numerous aberrations in immune function [38,39] and neural plasticity [40–42] and this work suggests that a nexus of these aberrations may be juvenile experience-dependent plasticity, which is increasingly postulated as an important locus of neurodevelopmental risk [7,8].…”

Section: Discussionmentioning

confidence: 99%

“…Both juvenile and Lynx1 −/− mice have elevated experience-dependent plasticity, whereas adult wild-type mice have reduced plasticity. Transcriptional data was derived from publicly available data (GSE89757 [14]). We used the well-established gene set enrichment approach from Enrichr [30] to determine known Gene Ontology Biological Processes relevant to the 35 putative plasticity genes (using a FDR < 0.05) and further assessed relevance of individual genes that mapped to genotyped variants using a literature-based approach.…”

Section: Methodsmentioning

confidence: 99%

“…Here, we use the mouse model of critical period visual plasticity [13] as our starting point to systematically identify genes related to neuroplasticity. This model has emerged as an indispensable model system to dissect the molecular mechanisms underlying functional cortical plasticity and whose transcriptional representation is functionally predictive [14]. Importantly, to control for age, elevated plasticity can be recapitulated in adult mice by genetically manipulating genes important for critical period plasticity.…”

Section: Introductionmentioning

confidence: 99%

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Loss-of-function of neuroplasticity-related genes confers risk for human neurodevelopmental disorders

Smith

Glicksberg

et al. 2017

Biocomputing 2018

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High and increasing prevalence of neurodevelopmental disorders place enormous personal and economic burdens on society. Given the growing realization that the roots of neurodevelopmental disorders often lie in early childhood, there is an urgent need to identify childhood risk factors. Neurodevelopment is marked by periods of heightened experience-dependent neuroplasticity wherein neural circuitry is optimized by the environment. If these critical periods are disrupted, development of normal brain function can be permanently altered, leading to neurodevelopmental disorders. Here, we aim to systematically identify human variants in neuroplasticity-related genes that confer risk for neurodevelopmental disorders. Historically, this knowledge has been limited by a lack of techniques to identify genes related to neurodevelopmental plasticity in a high-throughput manner and a lack of methods to systematically identify mutations in these genes that confer risk for neurodevelopmental disorders. Using an integrative genomics approach, we determined loss-of-function (LOF) variants in putative plasticity genes, identified from transcriptional profiles of brain from mice with elevated plasticity, that were associated with neurodevelopmental disorders. From five shared differentially expressed genes found in two mouse models of juvenile-like elevated plasticity (juvenile wild-type or adult Lynx1−/− relative to adult wild-type) that were also genotyped in the Mount Sinai BioMe Biobank we identified multiple associations between LOF genes and increased risk for neurodevelopmental disorders across 10,510 patients linked to the Mount Sinai Electronic Medical Records (EMR), including epilepsy and schizophrenia. This work demonstrates a novel approach to identify neurodevelopmental risk genes and points toward a promising avenue to discover new drug targets to address the unmet therapeutic needs of neurodevelopmental disease.

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Section: Methodssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss-of-function of neuroplasticity-related genes confers risk for human neurodevelopmental disorders

Smith

Glicksberg

et al. 2017

Biocomputing 2018

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Therapeutic Effects of Sodium Para-Aminosalicylic Acid on Cognitive Deficits and Activated ERK1/2-p90RSK/NF-κB Inflammatory Pathway in Pb-Exposed Rats

Lü

Zhang

Fang

et al. 2021

Biol Trace Elem Res

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Critical period plasticity-related transcriptional aberrations in schizophrenia and bipolar disorder

Smith

Readhead

Dudley

et al. 2019

Schizophrenia Research

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Childhood critical periods of experience-dependent plasticity are essential for the development of environmentally appropriate behavior and cognition. Disruption of critical periods can alter development of normal function and confer risk for neurodevelopmental disorders. While genes and their expression relevant to neurodevelopment are associated with schizophrenia, the molecular relationship between schizophrenia and critical periods has not been assessed systematically. Here, we apply a transcriptome-based bioinformatics approach to assess whether genes associated with the human critical period for visual cortex plasticity, a well-studied model of cortical critical periods, are aberrantly expressed in schizophrenia and bipolar disorder. Across two dozen datasets encompassing 522 cases and 374 controls, we find that the majority show aberrations in expression of genes associated with the critical period. We observed both hyper-and hypo-critical period plasticity phenotypes at the transcriptome level, which partially mapped to drug candidates that reverse the disorder signatures in silico. Our findings indicate plasticity aberrations in schizophrenia and their treatment may need to be considered in the context of subpopulations with elevated and others reduced plasticity. Future work should leverage ongoing consortia RNA-sequencing efforts to tease out the sources of plasticity-related transcriptional aberrations seen in schizophrenia, including true biological heterogeneity, interaction between normal development/aging and the disorder, and medication history. Our study also urges innovation towards direct assessment of visual cortex plasticity in humans with schizophrenia to precisely deconstruct the role of plasticity in this disorder.

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Integrative Analysis of Disease Signatures Shows Inflammation Disrupts Juvenile Experience-Dependent Cortical Plasticity

Abstract: Visual Abstract

Cited by 18 publications

References 70 publications

Loss-of-function of neuroplasticity-related genes confers risk for human neurodevelopmental disorders

Loss-of-function of neuroplasticity-related genes confers risk for human neurodevelopmental disorders

Therapeutic Effects of Sodium Para-Aminosalicylic Acid on Cognitive Deficits and Activated ERK1/2-p90RSK/NF-κB Inflammatory Pathway in Pb-Exposed Rats

Critical period plasticity-related transcriptional aberrations in schizophrenia and bipolar disorder

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