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Developmental protein kinase C hyper-activation results in microcephaly and behavioral abnormalities in zebrafish.

ABSTRACT: Susceptible genetic polymorphisms and altered expression levels of protein kinase C (PKC)-encoding genes suggest overactivation of PKC in autism spectrum disorder (ASD) development. To delineate the pathological role of PKC, we pharmacologically stimulated its activity during the early development of zebrafish. Results demonstrated that PKC hyper-activation perturbs zebrafish development and induces a long-lasting head size deficit. The anatomical and cellular analysis revealed reduced neural precursor proliferation and newborn neuron formation. ?-Catenin that is essential for brain growth is dramatically degraded. Stabilization of ?-catenin by gsk3? inhibition partially restores the head size deficit. In addition, the neuropathogenic effect of developmental PKC hyper-activation was further supported by the alterations in the behavioral domain including motor abnormalities, heightened stress reactivity and impaired habituation learning. Taken together, by causally connecting early-life PKC hyper-activation to these neuropathological traits and the impaired neurogenesis, these results suggest that PKC could be a critical pathway in ASD pathogenesis.

SUBMITTER: Liu T

PROVIDER: S-EPMC6199330 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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Developmental protein kinase C hyper-activation results in microcephaly and behavioral abnormalities in zebrafish.

Liu Taian T Shi Yujian Y Chan Matthew T V MTV Peng Gang G Zhang Quan Q Sun Xiao X Zhu Zeyao Z Xie Yuxin Y Sham Kathy W Y KWY Li Jianzhen J Liu Xiaodong X Ho Idy H T IHT Gin Tony T Lu Zhonghua Z Wu William K K WKK Cheng Christopher H K CHK

Translational psychiatry 20181023 1

Susceptible genetic polymorphisms and altered expression levels of protein kinase C (PKC)-encoding genes suggest overactivation of PKC in autism spectrum disorder (ASD) development. To delineate the pathological role of PKC, we pharmacologically stimulated its activity during the early development of zebrafish. Results demonstrated that PKC hyper-activation perturbs zebrafish development and induces a long-lasting head size deficit. The anatomical and cellular analysis revealed reduced neural pr ...[more]

PMID: 30352990

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Project description:Developmental consequences of prenatal drug exposure have been reported in many human cohorts and animal studies. The long-lasting impact on the offspring-including motor and cognitive impairments, cranial and cardiac anomalies and increased prevalence of ADHD-is a socioeconomic burden worldwide. Identifying the molecular changes leading to developmental consequences could help ameliorate the deficits and limit the impact. In this study, we have used zebrafish, a well-established behavioral and genetic model with conserved drug response and reward pathways, to identify changes in behavior and cellular pathways in response to developmental exposure to amphetamine, nicotine or oxycodone. In the presence of the drug, exposed animals showed altered behavior, consistent with effects seen in mammalian systems, including impaired locomotion and altered habituation to acoustic startle. Differences in responses seen following acute and chronic exposure suggest adaptation to the presence of the drug. Transcriptomic analysis of exposed larvae revealed differential expression of numerous genes and alterations in many pathways, including those related to cell death, immunity and circadian rhythm regulation. Differential expression of circadian rhythm genes did not correlate with behavioral changes in the larvae, however, two of the circadian genes, arntl2 and per2, were also differentially expressed at later stages of development, suggesting a long-lasting impact of developmental exposures on circadian gene expression. The immediate-early genes, egr1, egr4, fosab, and junbb, which are associated with synaptic plasticity, were downregulated by all three drugs and in situ hybridization showed that the expression for all four genes was reduced across all neuroanatomical regions, including brain regions implicated in reward processing, addiction and other psychiatric conditions. We anticipate that these early changes in gene expression in response to drug exposure are likely to contribute to the consequences of prenatal exposure and their discovery might pave the way to therapeutic intervention to ameliorate the long-lasting deficits.

Dataset Information

Developmental protein kinase C hyper-activation results in microcephaly and behavioral abnormalities in zebrafish.

Publications

Developmental protein kinase C hyper-activation results in microcephaly and behavioral abnormalities in zebrafish.

Similar Datasets

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