Neuron‐restrictive silencer factor/repressor element 1‐silencing transcription factor (NRSF/REST) controls spatial K⁺ buffering in primary cortical astrocytes

Abstract

Neuron‐restrictive silencer factor/repressor element 1 (RE1)‐silencing transcription factor (NRSF/REST) is a transcriptional repressor of a large cluster of neural genes containing RE1 motifs in their promoter region. NRSF/REST is ubiquitously expressed in non‐neuronal cells, including astrocytes, while it is down‐regulated during neuronal differentiation. While neuronal NRSF/REST homeostatically regulates intrinsic excitability and synaptic transmission, the role of the high NRSF/REST expression levels in the homeostatic functions of astrocytes is poorly understood. Here, we investigated the functional consequences of NRSF/REST deletion in primary cortical astrocytes derived from NRSF/REST conditional knockout mice (KO). We found that NRSF/REST KO astrocyte displayed a markedly reduced activity of inward rectifying K+ channels subtype 4.1 (Kir4.1) underlying spatial K+ buffering that was associated with a decreased expression and activity of the glutamate transporter‐1 (GLT‐1) responsible for glutamate uptake by astrocytes. The effects of the impaired astrocyte homeostatic functions on neuronal activity were investigated by co‐culturing wild‐type hippocampal neurons with NRSF/REST KO astrocytes. Interestingly, neurons experienced increased neuronal excitability at high firing rates associated with decrease after hyperpolarization and increased amplitude of excitatory postsynaptic currents. The data indicate that astrocytic NRSF/REST directly participates in neural circuit homeostasis by regulating intrinsic excitability and excitatory transmission and that dysfunctions of NRSF/REST expression in astrocytes may contribute to the pathogenesis of neurological disorders.

The homeostatic effects of the RE‐1 silencing transcription factor on cortical networks are altered under ictogenic conditions in the mouse

“…Moreover, it has been recently demonstrated that REST increases the strength of axo‐somatic inhibitory synapses onto excitatory neurons, while having no effect when the postsynaptic target cell was another inhibitory neuron 13 . A similar homeostatic effect was recently observed in astrocytes, where REST increases the transcription of the glutamate transporter GLT1 and favors the membrane exposure of the potassium channel Kir4.1, thus increasing glutamate and potassium clearance from the synaptic environment 14 …”

“…REST has been shown to play different roles under physiological conditions or under conditions of pathological hyperexcitability, ranging from homeostatic to pro‐epileptogenic effects 13,14,26,29,30 . However, a clear picture is still largely missing 29 .…”

“…11,12 3.5 | Deletion of Rest early in development attenuates the seizure severity in response to repeated administration of the convulsant pentylenetetrazole REST has been shown to play different roles under physiological conditions or under conditions of pathological hyperexcitability, ranging from homeostatic to pro-epileptogenic effects. 13,14,26,29,30 However, a clear picture is still largely missing. 29 To further elucidate the effects of the postnatal deletion of REST in neurons, we systemically administered the convulsant pentylenetetrazole (PTZ), known to alter network stability and homeostasis and simulate an epileptic-like condition by acting as a non-competitive antagonist of GABA A receptors.…”

“…13 A similar homeostatic effect was recently observed in astrocytes, where REST increases the transcription of the glutamate transporter GLT1 and favors the membrane exposure of the potassium channel Kir4.1, thus increasing glutamate and potassium clearance from the synaptic environment. 14 Notwithstanding these effects, the understanding of the role of REST in shaping neuronal networks is still largely incomplete, especially in the first phases of postnatal development. Hence, we here investigate the role of REST in shaping the neocortical excitatory/inhibitory (E/I) networks in the mouse early postnatal period under physiological conditions and test its activity under conditions of excitation/inhibition imbalance.…”

Restoring vision in adult amblyopia by enhancing plasticity through deletion of the transcriptional repressor REST

“…We have previously shown that REST KO primary astrocytes increase neuronal excitability by decreasing K + buffering and synaptic glutamate uptake. 56 In this context, the observed transcriptional increase of astrocyte Connexin-30, which during development contributes to the closure of the plasticity window, could represent a homeostatic mechanism during a phase of enhanced plasticity in adult life. It will be interesting to evaluate whether the plasticizing effects of REST downregulation occur, at least in part, through these mechanisms or whether there are different pathways leading to the reinstatement of V1 plasticity.…”