Cholinergic Synaptic Homeostasis Is Tuned by an NFAT-Mediated α7 nAChR-Kv4/Shal Coupled Regulatory System

• Published in: Cell reports (Cambridge) 2020-09, Vol.32 (10), p.108119-108119, Article 108119
• Main Authors: Eadaim, Abdunaser, Hahm, Eu-Teum, Justice, Elizabeth D., Tsunoda, Susan
• Format: Article
• Language: English
• Subjects: activity-dependent; cholinergic signaling; Drosophila; homeostatic synaptic plasticity; Kv4; NACHO; NFAT; Shal; synaptic homeostasis; α7 nAChR
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108119

Homeostatic synaptic plasticity (HSP) involves compensatory mechanisms employed by neurons and circuits to preserve signaling when confronted with global changes in activity that may occur during physiological and pathological conditions. Cholinergic neurons, which are especially affected in some pathologies, have recently been shown to exhibit HSP mediated by nicotinic acetylcholine receptors (nAChRs). In Drosophila central neurons, pharmacological blockade of activity induces a homeostatic response mediated by the Drosophila α7 (Dα7) nAChR, which is tuned by a subsequent increase in expression of the voltage-dependent Kv4/Shal channel. Here, we show that an in vivo reduction of cholinergic signaling induces HSP mediated by Dα7 nAChRs, and this upregulation of Dα7 itself is sufficient to trigger transcriptional activation, mediated by nuclear factor of activated T cells (NFAT), of the Kv4/Shal gene, revealing a receptor-ion channel system coupled for homeostatic tuning in cholinergic neurons. [Display omitted] •Inhibiting activity induces an increase in mEPSCs and Dα7 nAChR protein•Inhibiting activity induces upregulation of Kv4/Shal mRNA, protein, and current•Increasing Dα7 and/or NACHO is sufficient to induce upregulation of Kv4/Shal•Inactivity-induced upregulation of Kv4/Shal requires transcription factor NFAT Eadaim et al. show that in vivo reduction of cholinergic signaling in Drosophila neurons induces synaptic homeostasis mediated by Dα7 nAChRs. This upregulation of Dα7 induces Kv4/Shal gene expression mediated by nuclear factor of activated T cells (NFAT), revealing a receptor-ion channel system coupled for homeostatic tuning in cholinergic neurons.