An Intrinsic Transcriptional Program Underlying Synaptic Scaling during Activity Suppression

Abstract

Summary Homeostatic scaling allows neurons to maintain stable activity patterns by globally altering their synaptic strength in response to changing activity levels. Suppression of activity by blocking action potentials increases synaptic strength through an upregulation of surface AMPA receptors. Although this synaptic up-scaling was shown to require transcription, the molecular nature of the intrinsic transcription program underlying this process and its functional significance have been unclear. Using RNA-seq, we identified 73 genes that were specifically upregulated in response to activity suppression. In particular, Neuronal pentraxin-1 (Nptx1) increased within 6 h of activity blockade, and knockdown of this gene blocked the increase in synaptic strength. Notably, Nptx1 induction is mediated by calcium influx through the T-type Voltage-Gated Calcium Channel, as well as two transcription factors, SRF and ELK1. Taken together, these results uncover a transcriptional program that specifically operates when neuronal activity is suppressed, to globally coordinate the increase in synaptic strength.

Surfaceome dynamics during neuronal development and synaptic plasticity reveal system-wide surfaceome reorganization independent of global proteostasis

“…5e). In agreement with our data, it was previously reported that surface abundance of Nptx1 increases after 24 hours of TTX treatment and that inhibition of Nptx1 expression blocks synaptic upscaling 56 .…”

“…During synaptic upscaling total and surface abundance levels of Nptx1 increased (Fig. 5e), which recapitulates previous findings achieved with orthogonal approaches 56 . For synaptic downscaling, our data on Nptx2 (Fig.…”

“…Previous studies have mechanistically linked calcium influx with synaptic upscaling 55,56 . In support of this, we found that surface abundances of a number of voltage-gated calcium channels were significantly modulated in response to both homeostatic plasticity paradigms (e.g., Cacna2d3, Cacna1d) or only to downscaling (e.g., Cacna1c) ( Fig.…”

A gene expression program activated by neuronal inactivity

“…It would be interesting to know if the genes repressed by singing are induced by hyperpolarization or neuronal inactivity. Intriguingly, blocking neuronal activity in cultured mouse cortical neurons induced the expression of many genes (Schaukowitch et al, 2017), suggesting that a gene expression program that responds to neuronal inactivity exists in mammals.…”

Firing rate homeostasis occurs in the absence of neuronal activity-regulated transcription

“…We hypothesized that activity-regulated transcription would be required for firing rate homeostasis because it is required for several forms of homeostatic plasticity that could regulate firing rate. First, synaptic scaling, a multiplicative homeostatic change in the number of AMPA receptors at synapses (Turrigiano et al, 1998), is impaired by both acute blockade of transcription and by loss of specific activity-regulated genes (ARGs), including Arc, Nptx1, Plk2 , and Homer1a (Chowdhury et al, 2006; Diering et al, 2017; Hu et al, 2010; Ibata et al, 2008; Schaukowitch et al, 2017; Seeburg et al, 2008; Shepherd et al, 2006). In addition, activity-regulated transcription also homeostatically regulates excitatory/inhibitory (E/I) balance, or the relative strengths and numbers of excitatory and inhibitory synapses.…”