Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome
Raozhou Lin,
Lisa N. Learman,
M. Ali Bangash,
Tatiana Melnikova,
Erica Leyder,
Sai C. Reddy,
Nirinjini Naidoo,
Joo Min Park,
Alena Savonenko,
Paul F. Worley
Affiliations
Raozhou Lin
Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
Lisa N. Learman
Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
M. Ali Bangash
Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA; Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK
Tatiana Melnikova
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Erica Leyder
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Sai C. Reddy
Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
Nirinjini Naidoo
Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Joo Min Park
Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea; University of Science and Technology, Daejeon 34113, Republic of Korea; Corresponding author
Alena Savonenko
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Paul F. Worley
Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA; Corresponding author
Summary: 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.
