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

Jung Hwa Choi, Yun Mi Jeong, Sujin Kim, Boyoung Lee, Krishan Ariyasiri, Hyun Taek Kim, Seung Hyun Jung, Kyu Seok Hwang, Tae Ik Choi, Chul O. Park, Won Ki Huh, Matthias Carl, Jill A. Rosenfeld, Salmo Raskin, Alan Ma, Jozef Gecz, Hyung Goo Kim, Jin Soo Kim, Ho Chul Shin, Doo Sang ParkRobert Gerlai, Bradley B. Jamieson, Joon S. Kim, Karl J. Iremonger, Sang H. Lee, Hee Sup Shin, Cheol Hee Kim

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E1041-E1050
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number5
DOIs
Publication statusPublished - Jan 30 2018

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Keywords

  • Chemokine-like
  • anxiety
  • fear
  • knockout
  • zebrafish

ASJC Scopus subject areas

  • General

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