Genomic Decoding of Neuronal Depolarization by Stimulus-Specific NPAS4 Heterodimers

Cell. 2019 Oct 3;179(2):373-391.e27. doi: 10.1016/j.cell.2019.09.004.


Cells regulate gene expression in response to salient external stimuli. In neurons, depolarization leads to the expression of inducible transcription factors (ITFs) that direct subsequent gene regulation. Depolarization encodes both a neuron's action potential (AP) output and synaptic inputs, via excitatory postsynaptic potentials (EPSPs). However, it is unclear if distinct types of electrical activity can be transformed by an ITF into distinct modes of genomic regulation. Here, we show that APs and EPSPs in mouse hippocampal neurons trigger two spatially segregated and molecularly distinct induction mechanisms that lead to the expression of the ITF NPAS4. These two pathways culminate in the formation of stimulus-specific NPAS4 heterodimers that exhibit distinct DNA binding patterns. Thus, NPAS4 differentially communicates increases in a neuron's spiking output and synaptic inputs to the nucleus, enabling gene regulation to be tailored to the type of depolarizing activity along the somato-dendritic axis of a neuron.

Keywords: ARNT; ARNT2; CRISPR Cas9; NPAS4; dendrite; genome; hippocampus; immediate early gene; inducible transcription factor; local translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3' Untranslated Regions
  • Action Potentials*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • CA1 Region, Hippocampal / cytology
  • CA1 Region, Hippocampal / metabolism
  • CA1 Region, Hippocampal / physiology
  • Cells, Cultured
  • Excitatory Postsynaptic Potentials*
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism*
  • Neurons / physiology
  • Protein Multimerization
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Transcriptional Activation*


  • 3' Untranslated Regions
  • Basic Helix-Loop-Helix Transcription Factors
  • Npas4 protein, mouse
  • RNA, Messenger