Genomic decoding of neuronal depolarization by stimulus-specific NPAS4 heterodimers, RNA sequencing

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 with 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.细胞会响应显著的外部刺激，调控基因表达。在神经元中，去极化会诱导诱导型转录因子（inducible transcription factors, ITFs）的表达，这类转录因子可指导后续的基因调控过程。去极化可通过兴奋性突触后电位（excitatory postsynaptic potentials, EPSPs），同时编码神经元的动作电位（action potential, AP）输出与突触输入信息。然而目前尚不明确，不同类型的电活动是否可经由诱导型转录因子，转化为不同模式的基因组调控。本研究发现，小鼠海马神经元中的动作电位与兴奋性突触后电位，可触发两种空间分隔且分子机制迥异的诱导通路，最终促使诱导型转录因子NPAS4的表达。这两条通路最终分别形成刺激特异性的NPAS4异二聚体，二者展现出截然不同的DNA结合模式。综上，NPAS4可差异化地将神经元的锋电位输出与突触输入信号的变化传递至细胞核，使得基因调控能够适配神经元胞体-树突轴上不同类型的去极化活动。