Lateral entorhinal cortex inputs modulate hippocampal dendritic excitability by recruiting a local disinhibitory microcircuit

The lateral entorhinal cortex (LEC) provides information about multi-sensory environmental cues to the hippocampus through direct inputs to the distal dendrites of CA1 pyramidal neurons. A growing body of work suggests that LEC neurons perform important functions for episodic memory processing, coding for contextually-salient elements of an environment or the experience within it. However, we know little about the functional circuit interactions between LEC and the hippocampus. In this study, we combine functional circuit mapping and computational modeling to examine how long-range glutamatergic LEC projections modulate compartment-specific excitation-inhibition dynamics in hippocampal area CA1. We demonstrate that glutamatergic LEC inputs can drive local dendritic spikes in CA1 pyramidal neurons, aided by the recruitment of a disinhibitory vasoactive intestinal peptide (VIP)-expressing inhibitory neuron microcircuit. Our circuit mapping further reveals that, in parallel, LEC also recruits cholecystokinin (CCK)-expressing inhibitory neurons, which our model predicts act as a strong suppressor of dendritic spikes. These results provide new insight into a cortically-driven GABAergic microcircuit mechanism that gates non-linear dendritic computations, which may support compartment-specific coding of multi-sensory contextual features within the hippocampus. HIGHLIGHTSO_LISlice electrophysiology experiments investigate how lateral entorhinal cortex influences hippocampal area CA1 C_LIO_LILEC drives local spikes in distal dendrites but not in somata of CA1 pyramidal neurons C_LIO_LILEC inputs recruit VIP IN and CCK IN populations in CA1, but not SST INs C_LIO_LIComputational modeling and circuit manipulation experiments identify a VIP IN-mediated disinhibitory microcircuit for gating local dendritic spike generation C_LI IN BRIEFBilash et al. found that a distal cortical input is capable of driving local dendritic spikes in hippocampal pyramidal neurons. This dendritic spike generation is promoted by cortical recruitment of a local VIP interneuron-mediated disinhibitory microcircuit. Their results highlight new circuit mechanisms by which dynamic interaction of excitation, inhibition, and disinhibition support supralinear single-cell computations.