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

eLife

Alessandra Romei¹  Fabio Benfenati²  Gabriele Lignani³  Antonella Marte⁴  Daniele Ferrante⁵  Cosimo Prestigio⁵  Pierluigi Valente⁶  Pietro Baldelli⁶  Franco Onofri⁶ 

[1] Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy;Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy;IRCCS, Ospedale Policlinico San Martino, Genova, Italy;Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square House, London, United Kingdom;Department of Experimental Medicine, University of Genova, Genova, Italy;Department of Experimental Medicine, University of Genova, Genova, Italy;Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy;Department of Experimental Medicine, University of Genova, Genova, Italy;IRCCS, Ospedale Policlinico San Martino, Genova, Italy;

关键词: REST/NRSF;    GABAergic synapses;    BDNF;    synaptic homeostasis;    neural hyperactivity;    homeostatic plasticity;    NPAS4;    Mouse;   

DOI  :  10.7554/eLife.69058

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY