Figure 1. The revised model.

Synaptic activity at distal synapses can induce action potentials, which leads to Ca²⁺ influx in the soma to engage signaling cascades to the nucleus. Within the nucleus, genes respond to these incoming signals in two ways. The delayed IEGs undergo transcription initiation, which includes recruitment of general transcription factors (GTFs), Pol II and acquisition of histone modifications. Thus, they manifest relatively slower expression kinetics. The rapid IEGs are poised for rapid transcription within 2–5 minutes of activity due to the NELF-mediated Pol II stalling near their promoters. The presence of positive transcription elongation factor b (P-TEFb) promotes the entry of stalled Pol II into the productive elongation phase. Moreover, the stalling of the pioneer Pol II facilitates the recruitment of additional Pol II to these promoters pre-loaded with GTFs and active histone marks. Newly recruited Pol II can then re-initiate successive rounds of transcription resulting in a quick burst of the gene product. The exact signaling pathway leading up to Pol II productive elongation remains unknown. Also note that, upon transcription initiation, transient polymerase stalling can occur in all genes, including delayed IEGs. However, rapid IEGs are ‘armed’ to prolong this natural pause and utilize it to respond rapidly.