Parvalbumin cell state dynamics regulate gamma oscillations and are disrupted in Alzheimer's disease

Gamma oscillations are fundamental for cognitive processing, but the cellular and circuit dynamics that generate them remain poorly defined. Establishing a method for simultaneous calcium imaging and electrocorticography recordings in awake mice, we found that spontaneous gamma oscillations are accompanied by dynamic transitions between parvalbumin (PV) interneuron states. Rather than acting as a uniformly synchronized population, PV interneurons showed sequential recruitment, transient inactivation, and frequent transitions between activity states, indicating the formation of dynamic functional networks. In J20 Alzheimer's disease mice, these state transitions became dysregulated, leading to abnormal PV recruitment, impaired coupling between PV activity and gamma oscillations, and network hyperexcitability. Increasing interneuron excitability through expression of the voltage-gated sodium channel Nav1.1 restored PV cell dynamics, gamma oscillations, and network stability. These findings reveal dynamic PV cell states as an organizing feature of gamma oscillations and identify their disruption as a circuit mechanism of network dysfunction in Alzheimer's disease.