IF 25.9 | Cell Research | Fudan University Feifei Wang / Lan Ma Lab Discover Mechanism Maintaining the Stability of Memory Engram Networks

Release time：2025-09-19 15:27:17

The memory engram hypothesis proposes that a sparse population of neurons activated during memory formation (engrams) serves as the cellular basis for memory storage. Recent studies have shown that engrams storing the same memory display heterogeneity in synaptic connectivity and neuronal function—for example, the preferential recruitment of excitatory and inhibitory synaptic connections through Fos- and Npas4-dependent transcriptional pathways—which plays an important role in driving precise memory expression. However, the mechanisms by which established engram networks maintain stability to facilitate memory consolidation remain unclear.

On August 1, 2025, the team led by Feifei Wang and Lan Ma at Fudan University’s School of Basic Medical Sciences published an article in Cell Research entitled “Disturbed engram network caused by NPTX downregulation underlies aging-related contextual fear memory deﬁcits.” The study found that downregulation of the neuronal pentraxin family members NPTX1 and NPTX2—recognized molecular markers of cognitive impairment—induces destabilization of Fos/Npas4 engram circuits in the hippocampal dentate gyrus, thereby mediating memory deficits in aged mice.

https://www.nature.com/articles/s41422-025-01157-w

Specifically, the study revealed that NPTX1 and NPTX2 downregulation induces destabilization of Fos/Npas4 engram circuits in the hippocampal dentate gyrus (DG), which mediates age-related memory impairment. After contextual fear memory training, the expression of NPTX1 and NPTX2 increases, and they exhibit functional heterogeneity in stabilizing Fos and Npas4 engram circuits. NPTX1 binds to the potassium channel Kv7.2, promoting its membrane localization and restricting the responsiveness of Fos engram clusters to excitatory inputs from the medial entorhinal cortex (MEC), thereby facilitating fear memory expression. NPTX2, on the other hand, stabilizes the membrane expression of the AMPA receptor subunit GluA4 on PV interneurons, promoting the construction of inhibitory microcircuits between Npas4 engram clusters and PV interneurons, which prevents excessive generalization of fear memory. Restoring NPTX1 and NPTX2 expression within Fos and Npas4 engram clusters, respectively, rescues aging-induced impairments in memory retrieval and excessive generalization.

Memory encoding and retrieval require selective strengthening and activation of synaptic connections within engram circuits. However, during memory consolidation, memory engrams enter a dormant, non-activated state. How this dormant but stable state is maintained has remained elusive. This study innovatively reveals a mechanism by which engram networks are stabilized during consolidation by limiting network hyperexcitability, providing potential molecular and synapse-specific targets for ameliorating age-related cognitive impairments such as forgetting and overgeneralization.

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IF 25.9 | Cell Research | Fudan University Feifei Wang / Lan Ma Lab Discover Mechanism Maintaining the Stability of Memory Engram Networks

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IF 25.9 | Cell Research | Fudan University Feifei Wang / Lan Ma Lab Discover Mechanism Maintaining the Stability of Memory Engram Networks

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