Transcription-specific synaptic plasticity mediates engram computations

Neurons within memory engrams form sparse assemblies that encode memories. While transcriptional changes and learning-induced alterations in synaptic connectivity are known to be linked to memory formation, the relationship between transcription-specific changes in synaptic plasticity and the computational role of ensembles within the memory trace remains unclear.

This study investigates whether changes in synaptic plasticity triggered by the transcription of specific neuronal subsets contribute directly to the computations performed by ensembles during memory consolidation.

In the mouse dentate gyrus, ensembles defined by transcription factors Fos and Npas4 recruit distinct forms of synaptic plasticity. Ensembles activated by Fos-mediated transcription show increased activity in feedforward excitatory synapses, while those regulated by Npas4-dependent transcription engage plasticity in recurrent inhibitory synapses.

A spiking neural network model incorporating transcription-specific synaptic plasticity reveals that both Fos- and Npas4-dependent ensembles form following learning and persist after memory consolidation.

Model predictions indicate that disrupting Fos- or Npas4-dependent synaptic plasticity would impair memory generalization and discrimination, respectively. To test these predictions, the researchers selectively blocked Fos- or Npas4-dependent synaptic plasticity using acute deletion in the dentate gyrus. Contextual fear conditioning experiments with blocked ensembles supported the computational model's predictions, demonstrating that specific transcriptional programs govern the synaptic plasticity engaged by distinct ensembles and regulate memory computations.