Functional heterogeneity of medial septal GABAergic neurons in theta rhythm modulation and septo-hippocampal communication

The medial septum (MS) acts as a primary pacemaker for hippocampal theta rhythms. However, the functional diversity of MS GABAergic neurons and their roles in septo-hippocampal communication remain elusive. We combined optogenetic manipulation with multi-channel in vivo electrophysiological recordings in freely moving mice to characterize such heterogeneity. Rhythmic MS GABAergic neurons could be characterized into distinct functional subgroups based on their directional coupling with hippocampal theta oscillations. Granger causality analysis identified a "driver" subpopulation exerting strong causal influence on hippocampal theta, and a "follower" subgroup primarily receiving feedback from the hippocampus. Furthermore, optogenetic inhibition revealed two distinct response patterns, resembling "driver" and "follower" subpopulations. These findings provided evidence for a bidirectional septo-hippocampal inhibitory loop, suggesting that MS GABAergic neurons orchestrate theta rhythms through coordinated drive and feedback mechanisms.