Grid-Layout and Theta-Modulation of Layer 2 Pyramidal Neurons in Medial Entorhinal Cortex

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Science  21 Feb 2014:
Vol. 343, Issue 6173, pp. 891-896
DOI: 10.1126/science.1243028

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Entorhinal Cell Clusters

There is considerable interest in understanding the function of neurons in layer 2 of the medial entorhinal cortex and how they generate their unique firing patterns, which are important in the recall of facts and past events (see the Perspective by Blair). Ray et al. (p. 891, published online 23 January) investigated principal cells in layer 2 by immunoreactivity, projection patterns, microcircuit analysis, and assessment of temporal discharge properties in awake, freely moving animals. In tangential sections, pyramidal neurons were clustered into patches arranged in a hexagonal grid—very similar to the patterns observed in grid cell spatial firing. These patches received selective cholinergic innervation, which is critical for sustaining grid cell activity. Kitamura et al. (p. 896, published online 23 January) found that these cells drive a hippocampal circuit by projecting directly to the hippocampal CA1 area and synapsing with a distinct class of inhibitory neurons. This circuit provides feed-forward inhibition in combination with excitatory inputs from layer 3 cells of the medial entorhinal cortex, projecting to CA1 pyramidal cells to determine the strength and time window of temporal associative inputs.


Little is known about how microcircuits are organized in layer 2 of the medial entorhinal cortex. We visualized principal cell microcircuits and determined cellular theta-rhythmicity in freely moving rats. Non–dentate-projecting, calbindin-positive pyramidal cells bundled dendrites together and formed patches arranged in a hexagonal grid aligned to layer 1 axons, parasubiculum, and cholinergic inputs. Calbindin-negative, dentate-gyrus–projecting stellate cells were distributed across layer 2 but avoided centers of calbindin-positive patches. Cholinergic drive sustained theta-rhythmicity, which was twofold stronger in pyramidal than in stellate neurons. Theta-rhythmicity was cell-type–specific but not distributed as expected from cell-intrinsic properties. Layer 2 divides into a weakly theta-locked stellate cell lattice and spatiotemporally highly organized pyramidal grid. It needs to be assessed how these two distinct principal cell networks contribute to grid cell activity.

  • Present address: Werner Reichardt Centre for Integrative Neuroscience, Otfried-Müller-strasse 25, 72076 Tübingen, Germany.

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