PT - JOURNAL ARTICLE AU - Kocsis, Barnabás AU - Martínez-Bellver, Sergio AU - Fiáth, Richárd AU - Domonkos, Andor AU - Sviatkó, Katalin AU - Barthó, Péter AU - Freund, Tamás F. AU - Ulbert, István AU - Káli, Szabolcs AU - Varga, Viktor AU - Hangya, Balázs TI - Huygens synchronization of medial septal pacemaker neurons generates hippocampal theta oscillation AID - 10.1101/2021.01.22.427736 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.01.22.427736 4099 - http://biorxiv.org/content/early/2021/01/22/2021.01.22.427736.short 4100 - http://biorxiv.org/content/early/2021/01/22/2021.01.22.427736.full AB - Episodic learning and memory retrieval are critically dependent on a hippocampal 4-12 Hz oscillatory ‘clock’ signal, the theta oscillation. This clock is largely externally paced, by a network of GABAergic neurons in the medial septum (MS). Theoretical studies suggested a range of hypotheses how this network may achieve theta synchrony; however, experimental evidence is still lacking. By recording multiple single MS neurons and hippocampal local field potential oscillations simultaneously, with both acute and chronically implanted silicon probes, we show that MS pacemaker units oscillate at individual frequencies within the theta range in rodents. Synchronization of MS neuron frequencies, accompanied by an elevation of firing rates, was found to parallel hippocampal theta formation in multiple rodent model systems. This suggests a general mechanism for theta synchronization, akin to the synchronization of weakly coupled pendulum clocks observed by Huygens in the 17th century. We optogenetically identified the MS pacemaker units as parvalbumin-expressing GABAergic neurons, while the previously enigmatic MS glutamatergic neurons were mostly theta-activated non-rhythmic cells. Our data were consistent with a network model of partially connected single-compartment inhibitory pacemaker neurons, in which synchronization and de-synchronization in the frequency domain upon waxing and waning tonic excitatory drive was sufficient to toggle MS network output between theta and non-theta states. These results provide experimental and theoretical support to a frequency-synchronization mechanism for pacing hippocampal theta, which may serve as an inspirational prototype for the countless examples of synchronization processes in the central nervous system from Nematoda to Anthropoda to Chordate and Vertebrate phyla.Competing Interest StatementThe authors have declared no competing interest.