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Title 

Targeted knockout of a chemokine-like gene increases anxiety and fear responses

Authors 

J H ChoiY M JeongS KimB LeeK AriyasiriH T KimS H JungK S HwangT I ChoiC O ParkW K HuhM CarlJ A RosenfeldS RaskinA MaJ GeczH G KimJ S KimHo Chul ShinDoo-Sang ParkR GerlaiB B JamiesonK J IremongerS H LeeH S ShinC H Kim

Publisher 

National Academy of Sciences

Issue Date 

2018

Citation 

Proceedings of the National Academy of Sciences of the United States of America

Keywords 

anxietyChemokine-likefearknockoutzebrafish

Abstract 

Emotional responses, such as fear and anxiety, are fundamentally important behavioral phenomena with strong fitness components in most animal species. Anxiety-related disorders continue to represent a major unmet medical need in our society, mostly because we still do not fully understand the mechanisms of these diseases. Animal models may speed up discovery of these mechanisms. The zebrafish is a highly promising model organism in this field. Here, we report the identification of a chemokine-like gene family, samdori (sam), and present functional characterization of one of its members, sam2. We show exclusive mRNA expression of sam2 in the CNS, predominantly in the dorsal habenula, telencephalon, and hypothalamus. We found knockout (KO) zebrafish to exhibit altered anxiety-related responses in the tank, scototaxis and shoaling assays, and increased crh mRNA expression in their hypothalamus compared with wild-type fish. To investigate generalizability of our findings to mammals, we developed a Sam2 KO mouse and compared it to wild-type littermates. Consistent with zebrafish findings, homozygous KO mice exhibited signs of elevated anxiety. We also found bath application of purified SAM2 protein to increase inhibitory postsynaptic transmission onto CRH neurons of the paraventricular nucleus. Finally, we identified a human homolog of SAM2, and were able to refine a candidate gene region encompassing SAM2, among 21 annotated genes, which is associated with intellectual disability and autism spectrum disorder in the 12q14.1 deletion syndrome. Taken together, these results suggest a crucial and evolutionarily conserved role of sam2 in regulating mechanisms associated with anxiety.

ISSN 

0027-8424

Link 

http://dx.doi.org/10.1073/pnas.1707663115

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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