Fast spiking interneurons autonomously generate fast gamma oscillations in the medial entorhinal cortex with excitation strength tuning ING-PING transitions

Abstract

Gamma oscillations (40-140 Hz) play a fundamental role in neural coordination, facilitating communication and cognitive functions in the medial entorhinal cortex (mEC). While previous studies suggest that pyramidal-interneuron network gamma (PING) and interneuron network gamma (ING) mechanisms contribute to these oscillations, the precise role of inhibitory circuits remains unclear. Using optogenetic stimulation and whole-cell electrophysiology in acute mouse brain slices, we examined synaptic input and spike timing in neurons across layer II/III mEC. We found that fast-spiking interneurons exhibited robust gamma-frequency firing, while excitatory neurons engaged in gamma cycle skipping. Stellate and pyramidal cells received minimal recurrent excitation, whereas fast-spiking interneurons received strong excitatory input. Both excitatory neurons and fast-spiking interneurons received gamma frequency inhibition, emphasizing the role of recurrent inhibition in gamma rhythm generation. Notably, gamma activity was reduced, but persisted after AMPA/kainate receptor blockade, indicating that interneurons can sustain gamma oscillations independently through an ING mechanism. Selective activation of PV+ interneurons confirmed their ability to sustain fast gamma inhibition autonomously. To further assess the interplay of excitation and inhibition, we developed computational network models constrained by our experimental data. Simulations revealed that weak excitatory input to interneurons supports fast ING-dominated rhythms ([~]100-140 Hz), while strengthening excitatory drive induces a transition to slower PING-dominated oscillations (60-100 Hz). These findings highlight the dominant role of inhibitory circuits in sustaining gamma rhythms, demonstrate how excitation strength tunes the oscillatory regime, and refine models of entorhinal gamma oscillations critical for spatial memory processing. Significance StatementGamma oscillations in the medial entorhinal cortex (mEC) are essential for spatial navigation and memory, yet the mechanisms underlying their generation remain unresolved. Combining optogenetics, whole-cell electrophysiology, and computational modeling, we show that fast-spiking interneurons can autonomously sustain gamma rhythms via interneuron network gamma (ING). Blocking excitatory input reduced, but did not abolish gamma-frequency inhibition, and selective activation of PV+ interneurons confirmed their capacity to generate fast gamma independently. Modeling revealed that excitatory strength tunes the oscillatory regime, with weak excitation favoring fast ING and stronger excitation inducing slower pyramidal-interneuron network gamma (PING). These findings refine entorhinal gamma models and suggest a hybrid mechanism for switching between faster and slower gamma critical for spatial computation.