The muscarinic receptor agonist carbachol (CCh) can induce activity in the theta range (4–15 Hz) in the entorhinal cortex (EC), but the underlying network mechanisms remain unclear. Here, we investigated the interplay between interneurons and principal cells in the EC during CCh-induced theta-like field oscillations in an in vitro brain slice preparation using tetrodes. Field oscillations at 10.1 Hz (IQR = 9.5–10.9 Hz) occurred during bath application of CCh (100 μM; n = 32 experiments) and were associated with single-unit (n = 189) firing. Interneuron activity increased before principal cell activity at the onset of the oscillations and both interneurons and principal cells fired at specific oscillation phases with interneurons preceding principal cells, suggesting that interneurons modulate principal cell activity during such oscillations. The regularity of occurrence of CCh-induced oscillations was abolished by applying the GABAA receptor antagonist picrotoxin (100 μM; n = 13). These effects were accompanied by changes in firing with principal cells discharging action potentials before interneurons, along with a loss of preferred firing phase for principal cells in relation to the oscillation peaks. Blocking ionotropic glutamatergic transmission abolished CCh-induced field oscillations (n = 6), suggesting that ionotropic glutamatergic receptor signaling is necessary for their generation. Our results show that neuronal network interactions leading to CCh-induced theta-like field oscillations rest on the close interplay between interneurons and principal cells and that interneurons modulate principal cell activity during such oscillatory activity. Moreover, they underscore the role of ionotropic glutamatergic transmission in this type of oscillations.
