NMDA receptors regulate the firing rate set point of hippocampal circuits without altering single-cell dynamics

Highlights•Hippocampal firing is actively regulated around a network-level set point•Blocking NMDARs reduces this set point without impairing compensatory responses•Intrinsic plasticity of PV neurons mediates this novel NMDAR function via eEF2K•NMDARs regulate E/I ratio and network firing without affecting single-neuron driftSummaryUnderstanding how neuronal circuits stabilize their activity is a fundamental yet poorly understood aspect of neuroscience. Here, we show that hippocampal network properties, such as firing rate distribution and dimensionality, are actively regulated, despite perturbations and single-cell drift. Continuous inhibition of N-methyl-D-aspartate receptors (NMDARs) ex vivo lowers the excitation/inhibition ratio and network firing rates while preserving resilience to perturbations. This establishes a new network firing rate set point via NMDAR-eEF2K signaling pathway. NMDARs' capacity to modulate and stabilize network firing is mediated by excitatory synapses and the intrinsic excitability of parvalbumin-positive neurons, respectively. In behaving mice, continuous NMDAR blockade in CA1 reduces network firing without altering single-neuron drift or triggering a compensatory response. These findings expand NMDAR function beyond their canonical role in synaptic plasticity and raise the possibility that some NMDAR-dependent behavioral effects are mediated by their unique regulation of population activity set points.Graphical abstract