Ripple-selective GABAergic projection cells in the hippocampus

Ripples are brief high-frequency electrographic events with important roles in episodic memory. However, the in vivo circuit mechanisms coordinating ripple-related activity among local and distant neuronal ensembles are not well understood. Here, we define key characteristics of a long-distance projecting GABAergic cell group in the mouse hippocampus that selectively exhibits high-frequency firing during ripples while staying largely silent during theta-associated states when most other GABAergic cells are active. The high ripple-associated firing commenced before ripple onset and reached its maximum before ripple peak, with the signature theta-OFF, ripple-ON firing pattern being preserved across awake and sleep states. Controlled by septal GABAergic, cholinergic, and CA3 glutamatergic inputs, these ripple-selective cells innervate parvalbumin and cholecystokinin-expressing local interneurons while also targeting a variety of extra-hippocampal regions. These results demonstrate the existence of a hippocampal GABAergic circuit element that is uniquely positioned to coordinate ripple-related neuronal dynamics across neuronal assemblies. [Display omitted] •TORO cells are hippocampal GABAergic neurons•TORO cells rarely spike during theta states but burst during sharp-wave ripples•TORO cells express inhibitory M2Rs•TORO cells preferentially innervate INs and project extra-hippocampally Szabo et al. identify a subset of hippocampal GABAergic cells with long-range projections and unique activity dynamics. Theta-OFF/ripple-ON (TORO) cells are virtually silent during locomotion and REM sleep theta but fire vigorously during sharp-wave ripples. TORO cells receive CA3 glutamatergic, septal GABAergic, and inhibitory cholinergic inputs and target interneurons.