A Novel Mechanism for the Grid-to-Place Cell Transformation Revealed by Transgenic Depolarization of Medial Entorhinal Cortex Layer II

Abstract

The spatial receptive fields of neurons in medial entorhinal cortex layer II (MECII) and in the hippocampus suggest general and environment-specific maps of space, respectively. However, the relationship between these receptive fields remains unclear. We reversibly manipulated the activity of MECII neurons via chemogenetic receptors and compared the changes in downstream hippocampal place cells to those of neurons in MEC. Depolarization of MECII impaired spatial memory and elicited drastic changes in CA1 place cells in a familiar environment, similar to those seen during remapping between distinct environments, while hyperpolarization did not. In contrast, both manipulations altered the firing rate of MEC neurons without changing their firing locations. Interestingly, only depolarization caused significant changes in the relative firing rates of individual grid fields, reconfiguring the spatial input from MEC. This suggests a novel mechanism of hippocampal remapping whereby rate changes in MEC neurons lead to locational changes of hippocampal place fields.

Grid scale drives the scale and long-term stability of place maps

“…Computational and experimental works have suggested that place cell remapping can be induced by rotation or phase shift in the grid pattern, or a change in grid firing rate 3, 21, 39 . However, we found that grid cells remained spatially stable across days in iWT and iCre-KO mice (Supplementary Fig.…”

“…Importantly, previous studies that examined the impact of grid cells on place coding involved a total loss of grid cells 9–11, 17, 19 , degradation of the grid structure 15, 16, 20 , or manipulation of multiple functionally defined cell-types 21 . This could obscure how grid cells normally effect place cells when their periodicity is intact.…”

Spatial representation in the hippocampal formation: a history

“…Place fields have been reported to persist when the spatially periodic firing pattern of MEC grid cells is compromised by inactivation of septal inputs 181,182 , and in young animals, place cells acquire stable firing fields before sharp periodic firing patterns emerge in grid cells 183,184 . Inactivation or damage of the MEC is not sufficient to disrupt place cell firing in the hippocampus 128,131,132,185 . However, neither of these observations rules out grid cells as a key determinant of spatially selective firing in the hippocampus.…”

“…Place fields may be formed from any of these inputs, by more than a single mechanism. Even pure rate changes among the MEC inputs are sufficient to completely alter the activity distribution among place cells in the hippocampus 185 . The mechanism for grid cell to place cell or place cell to grid cell transformation may have many faces, and understanding it may require that circuitry is disentangled at a higher level of detail, possibly in terms of inputs and outputs of individual cells.…”

Heterogeneity in hippocampal place coding

“…Confirming that MEC plays a key role in shaping place cell responses, both transient optogenetic inactivation and chemogenetic depolarization of MEC evoke place cell remapping [41 • ,42]. However, causally linking remapping to changes in the activity of specific MEC cell-types remains a formidable goal as, presently, there are no genetic markers by which to distinguish these functional cell-types.…”