Hippocampus and Entorhinal Cortex Recruit Cholinergic and NMDA Receptors Separately to Generate Hippocampal Theta Oscillations

Although much progress has been made in understanding type II theta rhythm generation under urethane anesthesia, less is known about the mechanisms underlying type I theta generation during active exploration. To better understand the contributions of cholinergic and NMDA receptor activation to type I theta generation, we recorded hippocampal theta oscillations from freely moving mice with local infusion of cholinergic or NMDA receptor antagonists to either the hippocampus or the entorhinal cortex (EC). We found that cholinergic receptors in the hippocampus, but not the EC, and NMDA receptors in the EC, but not the hippocampus, are critical for open-field theta generation and Y-maze performance. We further found that muscarinic M1 receptors located on pyramidal neurons, but not interneurons, are critical for cholinergic modulation of hippocampal synapses, theta generation, and Y-maze performance. These results suggest that hippocampus and EC neurons recruit cholinergic-dependent and NMDA-receptor-dependent mechanisms, respectively, to generate theta oscillations to support behavioral performance. [Display omitted] •Entorhinal NMDA receptors are important for theta generation in freely moving mice•Hippocampal cholinergic receptors are important for theta generation•Muscarinic M1 receptors on pyramidal neurons are important for theta generation Gu et al. find that the entorhinal cortex and hippocampus recruit NMDA-receptor-dependent and cholinergic-dependent mechanisms, respectively, to generate hippocampal theta oscillations in freely moving mice. Muscarinic M1 receptors on pyramidal neurons are important for theta generation, providing potential cellular mechanisms underlying theta generation.