Activity-Induced Regulation of Synaptic Strength through the Chromatin Reader L3mbtl1
Wenjie Mao,
Anna C. Salzberg,
Motokazu Uchigashima,
Yuto Hasegawa,
Hanno Hock,
Masahiko Watanabe,
Schahram Akbarian,
Yuka Imamura Kawasawa,
Kensuke Futai
Affiliations
Wenjie Mao
Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605-2324, USA
Anna C. Salzberg
Department of Pharmacology, Department of Biochemistry and Molecular Biology, and Institute for Personalized Medicine, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
Motokazu Uchigashima
Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605-2324, USA; Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
Yuto Hasegawa
Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605-2324, USA
Hanno Hock
Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School,185 Cambridge Street, Boston, MA 02114, USA
Masahiko Watanabe
Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
Schahram Akbarian
Mount Sinai Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA
Yuka Imamura Kawasawa
Department of Pharmacology, Department of Biochemistry and Molecular Biology, and Institute for Personalized Medicine, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
Kensuke Futai
Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605-2324, USA; Corresponding author
Summary: Homeostatic synaptic downscaling reduces neuronal excitability by modulating the number of postsynaptic receptors. Histone modifications and the subsequent chromatin remodeling play critical roles in activity-dependent gene expression. Histone modification codes are recognized by chromatin readers that affect gene expression by altering chromatin structure. We show that L3mbtl1 (lethal 3 malignant brain tumor-like 1), a polycomb chromatin reader, is downregulated by neuronal activity and is essential for synaptic response and downscaling. Genome-scale mapping of L3mbtl1 occupancies identified Ctnnb1 as a key gene downstream of L3mbtl1. Importantly, the occupancy of L3mbtl1 on the Ctnnb1 gene was regulated by neuronal activity. L3mbtl1 knockout neurons exhibited reduced Ctnnb1 expression. Partial knockdown of Ctnnb1 in wild-type neurons reduced excitatory synaptic transmission and abolished homeostatic downscaling, and transfecting Ctnnb1 in L3mbtl1 knockout neurons enhanced synaptic transmission and restored homeostatic downscaling. These results highlight a role for L3mbtl1 in regulating homeostasis of synaptic efficacy. : Synaptic homeostasis is crucial for maintaining proper neuronal excitability and excitatory/inhibitory balance in the brain. Mao et al. report that an activity-dependent chromatin reader protein is required for homeostatic control of synaptic strength through the regulation of downstream target gene Ctnnb1. Keywords: homeostatic plasticity, synaptic scaling, chromatin reader, glutamate receptor, synaptic transmission, hippocampus, neuronal activity
