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bioRxiv · 10.1101/2021.04.21.440758

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

Prestigio, C.·Ferrante, D.·Marte, A.·Romei, A.·Lignani, G.·Onofri, F.·Valente, P.·Benfenati, F.·Baldelli, P.
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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 enhancement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs. Notably, this effect was only observed at inhibitory-onto-excitatory neuron synapses, whose density increased at perisomatic sites, demonstrating a strict target-selectivity. These effects were occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and BDNF gene programs. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at preserving physiological levels of neuronal activity in front of the ever-changing environment. Impact StatementThis work elucidates the mechanisms by which the transcriptional regulator REST/NRSF selectively upregulates GABAergic transmission onto excitatory neurons in response to hyperactivity to rescue neuronal homeostasis.

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Prestigio, C., Ferrante, D., Marte, A., Romei, A., Lignani, G., Onofri, F., Valente, P., Benfenati, F., Baldelli, P.. 2021-04-21. REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion. https://doi.org/10.1101/2021.04.21.440758

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