Novel GABAergic circuits mediating excitation/inhibition of Cajal-Retzius cells in the developing hippocampus

Cajal-Retzius cells are a class of neurons believed to play critical roles during cortical development. However, their network computational functions remain poorly understood. Although work in the neocortex and hippocampus has shown that Cajal-Retzius cells receive predominantly, if not exclusively, spontaneous GABA_A receptor-mediated input, the cellular sources originating these events remain unclear. However, a precise definition of the presynaptic GABAergic interneurons contacting Cajal-Retzius cells is important to understand the microcircuits and network patterns controlling their activation. Here, we have taken advantage of electrophysiological and anatomical techniques applied to mouse hippocampal slices in vitro to directly address this question. Our paired recording experiments indicate that Cajal-Retzius cells receive small-amplitude, kinetically slow synaptic input from stratum lacunosum-moleculare interneurons, anatomically identified as neurogliaform cells. In addition, a convergence of optogenetic, electrophysiological, and pharmacological experiments shows that Cajal-Retzius cells receive GABAergic input from oriens lacunosum-moleculare cells and that this input has different physiological properties (i.e., larger amplitude and faster kinetics) from the one provided by neurogliaform cells. Last, we show that GABAergic evoked synaptic input onto Cajal-Retzius cells may either increase their excitability and trigger action potentials or inhibit spontaneous firing by depolarization block. We propose that the specific type of response depends on both the membrane potential of Cajal-Retzius cells and the kinetics of the received GABAergic input. In conclusion, we have unraveled a novel hippocampal microcircuit with complex GABAergic synaptic signaling, which we suggest mayplay a role in the refinement of the hippocampal network and connections during development.