Homeostatic preservation of action potential waveform by Notch and Nerfin-1

Central neurons are post-mitotic and maintained throughout life in most organisms. Continuous, controlled turnover of ion channels is required to sustain neuron-type-specific firing and brain activity throughout the lifespan. Homeostatic mechanisms may be a point of molecular control. Yet the homeostatic mechanisms responsible for the preservation of neuron-type-specific firing remain generally unknown. We address this gap by characterizing the preservation of neuronal firing following the deletion of a potassium channel gene (Shal/Kv4). Patch-seq experiments and subsequent genetic analyses reveal widespread Notch signaling-dependent transcriptional changes, including a required function for Nervous Fingers 1 (Nerfin-1), a transcription factor previously implicated in cell fate restriction. Remarkably, this homeostatic signaling system is without a baseline effect yet restores individual action potential waveforms with millisecond precision following the loss of Shal. We propose that Notch/Nerfin-1 signaling drives a transcriptional state change necessary for the homeostatic preservation of action potential waveform, with stable brain activity being an emergent property.