Olfactory bulb circuits drive ketamine-enhanced high-frequency oscillations via kainate and GABAergic mechanisms.

Ketamine rapidly reorganizes fast brain rhythms differently across cortical networks. In freely moving rats, neocortical gamma power increased broadly, while the olfactory bulb showed suppressed gamma alongside robust high-frequency oscillations (HFO; 130-180 Hz). Local blockade of non-NMDA glutamate receptors in the olfactory bulb suppressed ketamine-enhanced HFO in the bulb, ventral striatum, and prefrontal cortex without affecting neocortical gamma, indicating separate circuit mechanisms. Within the bulb, a kainate receptor antagonist markedly reduced HFO, while AMPA receptor blockade had minimal effect. Blocking GABA-A receptors reduced HFO power while increasing gamma power, showing that fast inhibition is necessary for HFO expression. The findings suggest that tonic kainate-dependent depolarization recruits interneurons to generate an inhibitory network rhythm that drives HFO propagation through olfactory-limbic circuits.

Study at a glance

Abstract

Ketamine produces rapid antidepressant effects accompanied by marked changes in fast brain rhythms. High-frequency oscillations (HFO; 130-180 Hz) are an increasingly recognized signature of ketamine across species. However, their relationship to classical gamma activity and their circuit-level organization remain unclear. Using simultaneous multiregion recordings in freely moving male Wistar rats, we show that ketamine differentially reorganizes fast oscillations across cortical networks: neocortical gamma power increased broadly, whereas the olfactory bulb (OB) showed suppressed gamma alongside robust, highly coherent HFO. Local OB infusion of the non-NMDA ionotropic glutamate receptor antagonists CNQX or NBQX suppressed ketamine-enhanced HFO both locally and in ventral striatum and prefrontal cortex without affecting neocortical gamma, indicating dissociable circuit mechanisms. Within the OB, the kainate receptor antagonist UBP310 markedly reduced HFO, whereas AMPA receptor blockade with IEM-1925 had minimal effect. Local GABA-A receptor blockade with bicuculline significantly reduced HFO power while increasing gamma power, demonstrating that intact fast inhibition is required for HFO expression. Based on these findings and known receptor kinetics, we propose that tonic kainate-dependent depolarization recruits interneurons to generate an inhibitory network rhythm, producing synchronized bursts that modulate mitral cell dendrites and drive HFO propagation through olfactory-limbic circuits.