Distinct Fos- and Npas4-mediated synaptic plasticity crucial for memory consolidation

Experiences are encoded in sparse neuronal ensembles that can be defined by the transcription activation of immediate-early genes such as Fos and Npas4. The Fos+ and Npas4+ neuronal ensembles within an engram have been reported to recruit distinct synaptic plasticity mechanisms. However, it remains unknown whether and how Fos- and Npas4-mediated synaptic plasticity support memory consolidation. Here we provide experimental and computational evidence that Fos+ and Npas4+ neuronal ensembles coordinate different excitatory and inhibitory synaptic plasticity mechanisms to promote memory consolidation. Using contextual fear conditioning and electrophysiology recordings, we found that Fos+ and Npas4+ granule cells in the hippocampal dentate gyrus recruit distinct forms of inhibitory synaptic plasticity from parvalbumin (PV+) and cholecystokinin (CCK+) interneurons. Based on these experimental findings, we proposed a computational model in which Fos+ and Npas4+ neurons have specific combinations of excitatory and inhibitory plasticity that led to the emergence of engram selectivity during memory consolidation. In our network model, Fos-mediated plasticity enabled cross-region synaptic coupling — a feature thought to support coupled engram reactivations in systems consolidation of memory. On the other hand, Npas4-mediated plasticity rendered engram ensembles highly robust to reactivation noise during consolidation in our simulations. Our model also predicted that the composition and selectivity of Fos+ and Npas4+ engram ensembles evolve distinctly with time and that blocking the plasticity of PV+ and CCK+ interneurons disrupts memory consolidation. Our work reveals that transcriptionally-defined neuronal ensembles within an engram have both shared and complementary roles in memory consolidation. These results highlight the impact of cell-type-specific synaptic plasticity on a wide range of computational and behavioral functions.