Department of Experimental Medicine, University of Genova, Genova, Italy.
Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy.
Elife. 2021 Dec 2;10:e69058. doi: 10.7554/eLife.69058.
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 and 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.
阻遏元件 1 沉默转录/神经元抑制因子（REST/NRSF）调控着数百种神经元特异性基因。我们曾表明，REST/NRSF 可下调谷氨酸能传递以响应过度兴奋，从而有助于神经元的内稳态。然而，REST/NRSF 的内稳态作用是否也涉及 GABA 能传递尚不清楚。在这里，我们发现，过度兴奋诱导的 REST/NRSF 激活引发 GABA 能抑制的内稳态重排，导致培养的海马神经元中小型抑制性突触后电流（IPSCs）的频率增加和诱发 IPSC 的幅度增加。值得注意的是，这种效应仅限于抑制性到兴奋性神经元突触，其在体细胞水平上的密度增加，而在树突区域减少，表现出复杂的靶区和区域选择性。躯体抑制的放大被 TrkB 受体抑制所阻断，并且源自 和 基因程序的协调和顺序激活。相反，树突抑制的缩小依赖于 REST，但不依赖于 BDNF。这些发现强调了 REST/NRSF 在转录反应中的核心作用，旨在针对不断变化的环境，挽救网络活动的生理水平。
