Fan cells in lateral entorhinal cortex directly influence medial entorhinal cortex through synaptic connections in layer 1
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eLife assessment
This fundamental work reveals a novel direct projection from the lateral entorhinal cortex to the medial entorhinal cortex. Using multiple techniques, the authors provide compelling evidence that fan cells from the lateral entorhinal cortex project to superficial neurons in the medial entorhinal cortex. This newly identified connection may support the combination of spatial inputs with sensory or high-order signals, providing novel insight into potentially how the 'what' (lateral entorhinal cortex) and 'where' (medial entorhinal cortex) features of memory are incorporated.
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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, in mice, 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 inputs from fan cells 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 GABA A and GABA B receptors, respectively. Inputs from fan cells 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.
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eLife assessment
This fundamental work reveals a novel direct projection from the lateral entorhinal cortex to the medial entorhinal cortex. Using multiple techniques, the authors provide compelling evidence that fan cells from the lateral entorhinal cortex project to superficial neurons in the medial entorhinal cortex. This newly identified connection may support the combination of spatial inputs with sensory or high-order signals, providing novel insight into potentially how the 'what' (lateral entorhinal cortex) and 'where' (medial entorhinal cortex) features of memory are incorporated.
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Reviewer #1 (Public Review):
In this manuscript, Vandrey et al characterize axonal projections from fan cells in the lateral entorhinal cortex (LEC) to the medial entorhinal cortex (MEC). Their findings are important and the manuscript is well-written.
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Reviewer #2 (Public Review):
In this report, the authors evaluate the possibility that LEC neurons send direct projection onto MEC cells, thus revising the current model of LEC and MEC sending independent inputs to the DG, whose role is to eventually combine both inputs. They demonstrate that L2a SCs in the LEC that receive neocortical inputs, send collaterals to L1 MEC, thus identifying a new indirect route by which MEC neurons can integrate cortical information. Vandrey et al., show that L2a SCs in the LEC contact directly with both inhibitory and excitatory cells in the MEC, but superficial principal cells with a higher probability. Therefore, L2 LEC neurons can exert control of the MEC activity, thus shaping its inputs to the hippocampus. By controlling the firing activity in superficial MEC, this newly identified LEC-MEC connection …
Reviewer #2 (Public Review):
In this report, the authors evaluate the possibility that LEC neurons send direct projection onto MEC cells, thus revising the current model of LEC and MEC sending independent inputs to the DG, whose role is to eventually combine both inputs. They demonstrate that L2a SCs in the LEC that receive neocortical inputs, send collaterals to L1 MEC, thus identifying a new indirect route by which MEC neurons can integrate cortical information. Vandrey et al., show that L2a SCs in the LEC contact directly with both inhibitory and excitatory cells in the MEC, but superficial principal cells with a higher probability. Therefore, L2 LEC neurons can exert control of the MEC activity, thus shaping its inputs to the hippocampus. By controlling the firing activity in superficial MEC, this newly identified LEC-MEC connection may participate in the combination of spatial inputs with sensory and high-order signals and thus "provide a substrate for the integration of 'what' and 'where' components of episodic memories".
The manuscript is well-written and the experimental design is well-suited to answer the question. The data presented here is a thorough, well-explained, and detailed work describing a new communication route between the LEC and MEC.
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Reviewer #3 (Public Review):
The manuscript by Vandry et al analyzes the circuitry connecting LEC to MEC, identifying a new connection with potential significance for cortico-hippocampal coding and memory. Using a combination of viral tracing, patch-clamp electrophysiology, and optogenetics, the authors reveal a new excitatory projection from Fan cells of LEC layer 2 to superficial neurons of MEC. Specifically, Fan cells synapse on MEC L2 stellate and pyramidal neurons, as well as layer 1 and layer 2 local interneurons, which provide fast and slow local feedforward inhibition to MEC excitatory neurons. The authors observe substantial cell-to-cell heterogeneity in the excitatory-to-inhibitory ratio, which does not seem to be a result of anatomical location. This heterogeneity is conserved during theta-like stimulation. This new …
Reviewer #3 (Public Review):
The manuscript by Vandry et al analyzes the circuitry connecting LEC to MEC, identifying a new connection with potential significance for cortico-hippocampal coding and memory. Using a combination of viral tracing, patch-clamp electrophysiology, and optogenetics, the authors reveal a new excitatory projection from Fan cells of LEC layer 2 to superficial neurons of MEC. Specifically, Fan cells synapse on MEC L2 stellate and pyramidal neurons, as well as layer 1 and layer 2 local interneurons, which provide fast and slow local feedforward inhibition to MEC excitatory neurons. The authors observe substantial cell-to-cell heterogeneity in the excitatory-to-inhibitory ratio, which does not seem to be a result of anatomical location. This heterogeneity is conserved during theta-like stimulation. This new connection allows for a kind of unidirectional "cross-talk", in which LEC can speak to MEC prior to or during communication of both of these regions with the hippocampus.
The results are generally clear and well-contextualized by the text. The authors use multiple complementary anatomical methods to identify the LEC to MEC connection, all of which agree. This is supported by the electrophysiological measurements, which are straightforward and generally convincing. The results provide important data for understanding the previously underappreciated reciprocal circuitry between MEC and LEC, which, as the authors nicely lay out in the introduction, is likely key for understanding the operation of memory networks.
The work described in this manuscript, which is all in vitro, appears nicely conducted and solid and is well presented and analyzed appropriately. However, it is not clear how this information can be used to glean an improved understanding of how LEC and MEC interact in the intact system, which is obviously the big question. In vivo experiments of this kind are quite challenging, but without some observation or perturbation of circuit dynamics in the intact animal, or at the very least a compelling model of how hippocampal/memory information processing is influenced by this new circuit, it may be hard for readers to know what to make of the new data the authors provide.
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