Neurogliaform cells mediate feedback inhibition in the medial entorhinal cortex.

Layer I of the medial entorhinal cortex (MEC) contains converging axons from several brain areas and dendritic tufts originating from principal cells located in multiple layers. Moreover, specific GABAergic interneurons are also located in the area, but their inputs, outputs, and effect on local network events remain elusive. Neurogliaform cells are the most frequent and critically positioned inhibitory neurons in layer I. They are considered to conduct feed-forward inhibition via GABAA and GABAB receptors on pyramidal cells located in several cortical areas. Using optogenetic experiments, we showed that layer I neurogliaform cells receive excitatory inputs from layer II pyramidal cells, thereby playing a critical role in local feedback inhibition in the MEC. We also found that neurogliaform cells are evenly distributed in layer I and do not correlate with the previously described compartmentalization ("cell islands") of layer II. We concluded that the activity of neurogliaform cells in layer I is largely set by layer II pyramidal cells through excitatory synapses, potentially inhibiting the apical dendrites of all types of principal cells in the MEC.

Somatostatin expressing GABAergic interneurons in the medial entorhinal cortex preferentially inhibit layerIII-V pyramidal cells.

GABA released from heterogeneous types of interneurons acts in a complex spatio-temporal manner on postsynaptic targets in the networks. In addition to GABA, a large fraction of GABAergic cells also express neuromodulator peptides. Somatostatin (SOM) containing interneurons, in particular, have been recognized as key players in several brain circuits, however, the action of SOM and its downstream network effects remain largely unknown. Here, we used optogenetics, electrophysiologic, anatomical and behavioral experiments to reveal that the dendrite-targeting, SOM+ GABAergic interneurons demonstrate a unique layer-specific action in the medial entorhinal cortex (MEC) both in terms of GABAergic and SOM-related properties. We show that GABAergic and somatostatinergic neurotransmission originating from SOM+ local interneurons preferentially inhibit layerIII-V pyramidal cells, known to be involved in memory formation. We propose that this dendritic GABA-SOM dual inhibitory network motif within the MEC serves to selectively modulate working-memory formation without affecting the retrieval of already learned spatial navigation tasks.