Fig. 9. Working model illustrating main findings.

During contextual fear memory learning (encoding), Fos transcription- and Npas4 transcription-dependent engram ensembles (F-RAM and N-RAM) are activated to preferentially recruit excitatory and inhibitory inputs. During memory consolidation, NPTX1 functions in F-RAM ensemble to restrict the response of this ensemble to MEC excitatory inputs, and NPTX2 functions in N-RAM ensemble to facilitate the recruitment of inhibitory inputs from PV⁺ interneurons. NPTX1 and NPTX2 cooperate to suppress engram network hyperactivity, thereby ensuring precise memory expression during retrieval. Downregulation of NPTX1 and NPTX2 in engram cells of aged mice contributes to destabilization of the engram network, resulting in contextual fear memory deficits.