Excitatory neurons in stratum radiatum provide an alternative pathway for excitation flow that escapes perisomatic inhibition

For over half a century, it has been postulated that the internal excitatory circuit in the hippocampus consists of three relay stations. Excitation arrives from the entorhinal cortex to the DG granule cells, is transmitted through the mossy fibers to CA3 pyramidal cells, and is then transmitted through Schaffer collaterals to CA1 pyramidal neurons. In all three structures (DG, CA3 and CA1), the activity of the excitatory neurons involved in the synaptic transmission of excitation are under the control of inhibitory basket neurons that are recruited into network activity via feed-forward and feed-back excitation. However, in the late 90s “stratum radiatum giant cells” were described as a novel type of neuron with the anatomical features of excitatory cells. Since then, the role of these cells in the hippocampal circuitry has not been well understood. Here, using optogenetic and electrophysiological techniques we characterized the functional location of these neurons within the hippocampal network. We show that: (i) the main excitatory drive to giant excitatory neurons in stratum radiatum (ExNR) comes via Schaffer collaterals; (ii) within the CA1 field, ExNR are not directly connected with local pyramidal cells, but provide massive and efficient excitatory input to parvalbumin positive (PV+) interneurons; (iii) ExNR are reciprocally innervated by bistratified cells, but not inhibited by backet interneurons; (iv) the efficiency of ExNR excitation to PV+ interneurons is sufficient for a single ExNR action potential to trigger massive inhibition of downstream CA1 pyramidal cells. Taken together, our data shows that ExNR constitute an alternative pathway of excitation for CA1 interneurons that avoids the burden of perisomatic inhibition. ### Competing Interest Statement The authors have declared no competing interest.