박주민 (기초과학연구원, UST) | 한빛사논문 > 한빛사

한빛사논문

조회839

기초과학연구원, UST

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Cell Reports, Volume 37, Issue 7, 16 November 2021, 110014 | https://doi.org/10.1016/j.celrep.2021.110014 Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome

Raozhou Lin¹, Lisa N. Learman¹, M. Ali Bangash^1,2, Tatiana Melnikova³, Erica Leyder³, Sai C. Reddy¹, Nirinjini Naidoo⁴, Joo Min Park^5,6,*, Alena Savonenko^3,*, Paul F. Worley^1,7,*

¹Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
²Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK
³Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
⁴Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
⁵Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea
⁶University of Science and Technology, Daejeon 34113, Republic of Korea
⁷Lead contact

^*Corresponding author

Abstract

Mutations of SHANK3 cause Phelan-McDermid syndrome (PMS), and these individuals can exhibit sensitivity to stress, resulting in behavioral deterioration. Here, we examine the interaction of stress with genotype using a mouse model with face validity to PMS. In Shank3ΔC/+ mice, swim stress produces an altered transcriptomic response in pyramidal neurons that impacts genes and pathways involved in synaptic function, signaling, and protein turnover. Homer1a, which is part of the Shank3-mGluR-N-methyl-D-aspartate (NMDA) receptor complex, is super-induced and is implicated in the stress response because stress-induced social deficits in Shank3ΔC/+ mice are mitigated in Shank3ΔC/+;Homer1a−/− mice. Several lines of evidence demonstrate that Shank3 expression is regulated by Homer1a in competition with crosslinking forms of Homer, and consistent with this model, Shank3 expression and function that are reduced in Shank3ΔC/+ mice are rescued in Shank3ΔC/+;Homer1a−/− mice. Studies highlight the interaction between stress and genetics and focus attention on activity-dependent changes that may contribute to pathogenesis.

논문정보

형식Research article
게재일2021년 11월 (BRIC 등록일 2021-11-19)
연구진국내(교신)+국외 연구진
분야 의약학 > 신경의학

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