A REST/NRSF-dependent transcriptional remodeling governs GABAergic synaptic upscaling induced by chronic hyperactivity

REST/NRFS (RE1-silencing transcription factor) has been initially identified as a negative transcription factor. Its target genes encode postsynaptic receptors, ion channels and transporters, neuropeptides and synaptic proteins. Evidences show that in mature neurons, REST can be upregulated by neuronal hyperactivity and works as a master epigenetic modulator, acting mostly as transcriptional repressor and, occasionally, as a transcriptional activator (Perera et al., 2015; Kallunki et al., 1998). We have previously demonstrated that REST is critical for the downscaling of intrinsic excitability in excitatory neurons subjected to prolonged elevation of electrical activity (Pozzi et al., 2013) and that it participates to the synaptic homeostasis of glutamatergic synapses by reducing their strength at the presynaptic level (Pecoraro-Bisogni et al., 2017). The aim of our work is to verify if REST plays a role in the synaptic homeostasis of GABAergic transmission evoked by hyperexcitability. Here we show that neuronal hyperactivity, obtained by treating for two days primary hippocampal neurons with 4-aminopyridine (4AP), induces a REST-dependent potentiation of the strength and number of somatic GABAergic synapses onto excitatory neurons, while the effect was lacking when the postsynaptic target cell was another inhibitory neuron. Our data suggest that the postsynaptic target specificity depends on a REST-dependent induction of a downstream transcription factor, NPAS4, known for its role in the development of inhibitory synapses, thanks to its capability of activating BDNF release from excitatory neurons upon hyperactivity (Lin et al. 2008). BDNF is synthetized only by excitatory neurons (Hofer et al., 1990). Thus, the retrograde action of BDNF, released from the soma of excitatory neurons onto the somatic GABAergic presynaptic contacts, could explain the observed postsynaptic target specificity of REST-action.