Fan cells in lateral entorhinal cortex directly influence medial entorhinal cortex through synaptic connections in layer 1

Abstract

Standard models for spatial and episodic memory suggest that the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC) send parallel independent inputs to the hippocampus, each carrying different types of information. Here, we evaluate the possibility that information is integrated between divisions of the entorhinal cortex prior to reaching the hippocampus. We demonstrate that fan cells in layer 2 (L2) of LEC that receive neocortical inputs, and that project to the hippocampal dentate gyrus, also send axon collaterals to layer 1 (L1) of the MEC. Activation of fan cell inputs evokes monosynaptic glutamatergic excitation of stellate and pyramidal cells in L2 of the MEC, typically followed by inhibition that contains fast and slow components mediated by GABAA and GABAB receptors, respectively. Fan cell inputs also directly activate interneurons in L1 and L2 of MEC, with synaptic connections from L1 interneurons accounting for slow feedforward inhibition of L2 principal cell populations. The relative strength of excitation and inhibition following fan cell activation differs substantially between neurons and is largely independent of anatomical location. Our results demonstrate that the LEC, in addition to directly influencing the hippocampus, can activate or inhibit major hippocampal inputs arising from the MEC. Thus, local circuits in the superficial MEC may combine spatial information with sensory and higher order signals from the LEC, providing a substrate for integration of what and where components of episodic memories.

Long-range inhibitory axons from medial entorhinal cortex target lateral entorhinal neurons projecting to the hippocampus

“…This is corroborated by our observations that SST + axons are missing from the return pathway connecting LEC to MEC, indicating that, even in the interplay between the entorhinal subregions, the inhibitory connection is exclusively unidirectional from MEC to LEC. Although other inhibitory neuron types could supply LEC-driven inhibition to MEC, it has recently been reported that the LEC–MEC pathway mainly consists of axons from PNiia, which provide excitatory synaptic inputs to principal neurons in superficial layers of MEC (Vandrey et al, 2022). Together, these observations predict that only LEC PNiia, but not their layer II counterparts in MEC, are under direct inhibitory control by the twin entorhinal subdivision and implies that entorhinal interactions are likely to have a contrasting influence on principal neuron activities in layer II of LEC and MEC.…”