REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion.

Cosimo Prestigio,Daniele Ferrante,Franco Onofri,Alessandra Romei,Pietro Baldelli,Antonella Marte,Gabriele Lignani,Pierluigi Valente,Fabio Benfenati

doi:10.7554/elife.69058

Abstract

The repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron-specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAergic transmission is also implicated in the homeostatic action of REST/NRSF is unknown. Here, we show that hyperactivity-induced REST/NRSF activation, triggers a homeostatic rearrangement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs in mouse cultured hippocampal neurons. Notably, this effect is limited to inhibitory-onto-excitatory neuron synapses, whose density increases at somatic level and decreases in dendritic regions, demonstrating a complex target- and area-selectivity. The upscaling of perisomatic inhibition was occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and Bdnf gene programs. On the opposite, the downscaling of dendritic inhibition was REST-dependent, but BDNF-independent. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at rescuing physiological levels of network activity in front of the ever-changing environment.

Highlights

The brain is characterized by a constant and fine homeostatic regulation of neuronal intrinsic excitability and synaptic strength aimed at keeping neuronal networks’ activity within a physiological range
To obtain evidence showing that the effects of repressor element 1-silencing transcription factor (REST) on perisomatic inhibitory transmission depend on Brain-derived neurotrophic factor (BDNF), we further studied the change in perisomatic synapses by combining REST inhibition with either TrkB inhibition or TrkB stimulation
Searching for a possible causal link between REST and BDNF, we focused our attention on NPAS4, a transcriptional activator recently demonstrated to induce a hyperactivity-induced increase in the number and strength of perisomatic inhibitory synapses onto excitatory neurons by inducing BDNF release from excitatory neurons (Bloodgood et al, 2013; Lin et al, 2008; Spiegel et al, 2014)

Summary

Introduction

The brain is characterized by a constant and fine homeostatic regulation of neuronal intrinsic excitability and synaptic strength aimed at keeping neuronal networks’ activity within a physiological range. Since neural excitation is believed to increase with age, the capability of REST to repress excitation- related genes (Pozzi et al, 2013) suggests that the activation of REST and reduction of excitatory neural activity could be responsible for slowing aging in humans (Zullo et al, 2019) These results are consistent with our previous studies, where we demonstrated that the hyperactivity-d ependent activation of REST furthers neuronal-n etwork homeostasis by downregulating intrinsic excitability and presynaptic function of excitatory neurons in response to chronic hyperactivity (Pecoraro-Bisogni et al, 2018; Pozzi et al, 2013). By acting at excitatory and inhibitory connections, REST activates a coordinated program that maintains brain circuits activity within physiological levels

Results

Discussion

Materials and methods