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

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.

journal_name

Proc Natl Acad Sci U S A

journal_title

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

authors

Choi JH,Jeong YM,Kim S,Lee B,Ariyasiri K,Kim HT,Jung SH,Hwang KS,Choi TI,Park CO,Huh WK,Carl M,Rosenfeld JA,Raskin S,Ma A,Gecz J,Kim HG,Kim JS,Shin HC,Park DS,Gerlai R,Jamieson BB,Kim JS,Iremonger KJ,Lee S

doi

10.1073/pnas.1707663115

subject

Has Abstract

pub_date

2018-01-30 00:00:00

pages

E1041-E1050

issue

eissn

0027-8424

issn

1091-6490

pii

1707663115

journal_volume

115

pub_type

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