Spike Afterpotentials Shape the In Vivo Burst Activity of Principal Cells in Medial Entorhinal Cortex.

Principal neurons in rodent medial entorhinal cortex (MEC) generate high-frequency bursts during natural behavior. While in vitro studies point to potential mechanisms that could support such burst sequences, it remains unclear whether these mechanisms are effective under in vivo conditions. In this study, we focused on the membrane-potential dynamics immediately following action potentials (APs), as measured in whole-cell recordings from male mice running in virtual corridors (Domnisoru et al., 2013). These afterpotentials consisted either of a hyperpolarization, an extended ramp-like shoulder, or a depolarization reminiscent of depolarizing afterpotentials (DAPs) recorded in vitro in MEC principal neurons. Next, we correlated the afterpotentials with the cells' propensity to fire bursts. All DAP cells with known location resided in Layer II, generated bursts, and their interspike intervals (ISIs) were typically between 5 and 15 ms. The ISI distributions of Layer-II cells without DAPs peaked sharply at around 4 ms and varied only minimally across that group. This dichotomy in burst behavior is explained by cell-group-specific DAP dynamics. The same two groups of bursting neurons also emerged when we clustered extracellular spike-train autocorrelations measured in real 2D arenas (Latuske et al., 2015). Apart from slight variations in grid spacing, no difference in the spatial coding properties of the grid cells across all three groups was discernible. Layer III neurons were only sparsely bursting (SB) and had no DAPs. As various mechanisms for modulating ion-channels underlying DAPs exist, our results suggest that temporal features of MEC activity can be altered while maintaining the cells' overall spatial tuning characteristics.SIGNIFICANCE STATEMENT Depolarizing afterpotentials (DAPs) are frequently observed in principal neurons from slice preparations of rodent medial entorhinal cortex (MEC), but their functional role in vivo is unknown. Analyzing whole-cell data from mice running on virtual tracks, we show that DAPs do occur during behavior. Cells with prominent DAPs are found in Layer II; their interspike intervals (ISIs) reflect DAP time-scales. In contrast, neither the rarely bursting cells in Layer III, nor the high-frequency bursters in Layer II, have a DAP. Extracellular recordings from mice exploring real 2D arenas demonstrate that grid cells within these three groups have similar spatial coding properties. We conclude that DAPs shape the temporal response characteristics of principal neurons in MEC with little effect on spatial properties.

Untethered firing fields and intermittent silences: Why grid-cell discharge is so variable.

Grid cells in medial entorhinal cortex are notoriously variable in their responses, despite the striking hexagonal arrangement of their spatial firing fields. Indeed, when the animal moves through a firing field, grid cells often fire much more vigorously than predicted or do not fire at all. The source of this trial-to-trial variability is not completely understood. By analyzing grid-cell spike trains from mice running in open arenas and on linear tracks, we characterize the phenomenon of "missed" firing fields using the statistical theory of zero inflation. We find that one major cause of grid-cell variability lies in the spatial representation itself: firing fields are not as strongly anchored to spatial location as the averaged grid suggests. In addition, grid fields from different cells drift together from trial to trial, regardless of whether the environment is real or virtual, or whether the animal moves in light or darkness. Spatial realignment across trials sharpens the grid representation, yielding firing fields that are more pronounced and significantly narrower. These findings indicate that ensembles of grid cells encode relative position more reliably than absolute position.