bioRxiv | 2019
RAI1 Regulates Activity-Dependent Nascent Transcription and Synaptic Scaling
Abstract
Long-lasting forms of synaptic plasticity such as synaptic scaling are critically dependent on transcription. Activity-dependent transcriptional dynamics in neurons, however, have not been fully characterized, because most previous efforts relied on measurement of steady-state mRNAs. Here, we profiled transcriptional dynamics of primary neuronal cultures undergoing network activity shifts using nascent RNA sequencing. We found pervasive transcriptional changes, in which ~45% of expressed genes respond to network activity shifts. Notably, the majority of these genes respond to increases or decreases of network activity uniquely, rather than reciprocally. We further linked the chromatin regulator Retinoic acid induced 1 (RAI1), the Smith-Magenis Syndrome gene, to the specific transcriptional program driven by reduced network activity. Finally, we show that RAI1 is essential for homeostatic synaptic upscaling but not downscaling. These results demonstrate the utility of bona fide transcription profiling to discover mechanisms of activity-dependent chromatin remodeling that underlie normal and pathological synaptic plasticity.