Transcription-specific synaptic plasticity mediates engram computations

Memory is encoded by sparse ensembles of neurons. While activity-dependent transcription and learning-induced synaptic plasticity are causally related to memory formation and recall, the link between the transcriptional regulation of synaptic plasticity and memory computations remains elusive. In particular, even though transcriptionally defined neuronal ensembles within a memory engram exhibit specific forms of synaptic plasticity and support distinct behavioral outputs, it is still unclear whether transcription-specific synaptic plasticity drives ensemble computations, rather than merely serving as a marker of ensemble identity. Here, we demonstrate that transcription-specific synaptic plasticity enables ensemble computations essential for learning-induced adaptive behaviors. In the mouse dentate gyrus (DG), we found that neuronal ensembles genetically defined by Fos-dependent transcription engage plasticity in feedforward excitatory synapses, whereas those defined by Npas4-dependent transcription engage plasticity in recurrent inhibitory synapses. We modeled spiking neural networks with transcription-specific synaptic plasticity and observed that Fos- and Npas4-dependent ensembles emerged following learning and stabilized with memory consolidation. Our computational model predicted that blocking Fos- or Npas4-dependent synaptic plasticity disrupts memory generalization and discrimination, respectively. By acutely deleting Fos or Npas4 in the DG to selectively block Fos- or Npas4-dependent synaptic plasticity, we conducted contextual fear conditioning experiments whose results supported our computational model's prediction. Our study provides causal evidence that specific transcriptional programs induced in distinct neuronal ensembles differentially engage synaptic plasticity and thereby regulate memory computations.