Papers

The consolidation of declarative memories is thought to rely on the offline reactivation of hippocampal cell assemblies during sharp-wave ripples (SWRs), which drives gradual neocortical redistribution of memory traces. While this process is conventionally framed in terms of neuronal plasticity, the role of glial cells—astrocytes and microglia—in regulating the temporal dynamics and fidelity of hippocampal replay remains largely unexplored. Here, we propose a tripartite model of memory consolidation in which astrocytic calcium signaling controls the precise timing of SWR-coupled replay, and microglial activity-dependent synaptic pruning sharpens the signal-to-noise ratio of reactivated memory ensembles. We hypothesize that during non-rapid eye movement (NREM) sleep, astrocytic release of D-serine and other gliotransmitters modulates NMDA-receptor-dependent plasticity at hippocampal-neocortical synapses, thereby gating the window of replay-driven systems transfer. Concurrently, microglia selectively eliminate weak or irrelevant synaptic connections tagged during replay, preventing the consolidation of noisy information. Disruption of either glial pathway leads to degraded replay fidelity and memory consolidation deficits, as observed in neuroinflammatory and neurodegenerative conditions. We outline a series of testable predictions and propose experimental approaches combining cell-type-specific optogenetics, in vivo two-photon imaging, and high-density electrophysiology to validate this framework. This perspective shifts the paradigm from a purely neuron-centric view of systems consolidation to one that integrates glial-neuronal interactions at the network level, with implications for understanding memory disorders and developing therapeutic interventions.