RAI1 Regulates Activity-Dependent Nascent Transcription and Synaptic Scaling
Patricia M. Garay,
Alex Chen,
Takao Tsukahara,
Jean Carlos Rodríguez Díaz,
Rafi Kohen,
J. Christian Althaus,
Margarete A. Wallner,
Roman J. Giger,
Kevin S. Jones,
Michael A. Sutton,
Shigeki Iwase
Affiliations
Patricia M. Garay
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Alex Chen
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Takao Tsukahara
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
Jean Carlos Rodríguez Díaz
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Rafi Kohen
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
J. Christian Althaus
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA
Margarete A. Wallner
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
Roman J. Giger
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
Kevin S. Jones
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
Michael A. Sutton
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author
Shigeki Iwase
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author
Summary: Long-lasting forms of synaptic plasticity such as synaptic scaling are critically dependent on transcription. Activity-dependent transcriptional dynamics in neurons, however, remain incompletely characterized because most previous efforts relied on measurement of steady-state mRNAs. Here, we use nascent RNA sequencing to profile transcriptional dynamics of primary neuron cultures undergoing network activity shifts. We find pervasive transcriptional changes, in which ∼45% of expressed genes respond to network activity shifts. We further link retinoic acid-induced 1 (RAI1), the Smith-Magenis syndrome gene, to the transcriptional program driven by reduced network activity. Remarkable agreement among nascent transcriptomes, dynamic chromatin occupancy of RAI1, and electrophysiological properties of Rai1-deficient neurons demonstrates the essential roles of RAI1 in suppressing synaptic upscaling in the naive network, while promoting upscaling triggered by activity silencing. These results highlight the utility of bona fide transcription profiling to discover mechanisms of activity-dependent chromatin remodeling that underlie normal and pathological synaptic plasticity.
