The superficial layers of the medial entorhinal cortex (MEC) are the major input to the hippocampus. The high proportion of spatially modulated cells, including grid cells and border cells, in these layers suggests that the MEC inputs to the hippocampus are critical for the representation of space in the hippocampus. However, selective manipulations of the MEC do not completely abolish hippocampal spatial firing. To therefore determine whether other hippocampal firing characteristics depend more critically on MEC inputs, we recorded from hippocampal CA1 cells in rats with MEC lesions. Strikingly, theta phase precession was substantially disrupted, even during periods of stable spatial firing. Our findings indicate that MEC inputs to the hippocampus are required for the temporal organization of hippocampal firing patterns and suggest that cognitive functions that depend on precise neuronal sequences within the hippocampal theta cycle are particularly dependent on the MEC.

During the crossing of the place field of a pyramidal cell in the rat hippocampus, the firing phase of the cell decreases with respect to the local theta rhythm. This phase precession is usually studied on the basis of data in which many place field traversals are pooled together. Here we study properties of phase precession in single trials. We found that single-trial and pooled-trial phase precession were different with respect to phase-position correlation, phase-time correlation, and phase range. Whereas pooled-trial phase precession may span 360°, the most frequent single-trial phase range was only ϳ180°. In pooled trials, the correlation between phase and position (r ϭ Ϫ0.58) was stronger than the correlation between phase and time (r ϭ Ϫ0.27), whereas in single trials these correlations (r ϭ Ϫ0.61 for both) were not significantly different. Next, we demonstrated that phase precession exhibited a large trial-to-trial variability. Overall, only a small fraction of the trial-to-trial variability in measures of phase precession (e.g., slope or offset) could be explained by other single-trial properties (such as running speed or firing rate), whereas the larger part of the variability remains to be explained. Finally, we found that surrogate single trials, created by randomly drawing spikes from the pooled data, are not equivalent to experimental single trials: pooling over trials therefore changes basic measures of phase precession. These findings indicate that single trials may be better suited for encoding temporally structured events than is suggested by the pooled data.

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High-frequency hippocampal network oscillations, or "ripples," are thought to be involved in episodic memory. According to current theories, memory traces are represented by assemblies of principal neurons that are activated during ripple-associated network states. Here we performed in vivo and in vitro experiments to investigate the synaptic mechanisms during ripples. We discovered postsynaptic currents that are phase-locked to ripples and coherent among even distant CA1 pyramidal neurons. These fast currents are consistent with excitatory postsynaptic currents (EPSCs) as they are observed at the equilibrium potential of Cl(-), and they display kinetics characteristic of EPSCs. Furthermore, they survived after intracellular blockade of GABAergic transmission and are effective to regulate the timing of action potentials. In addition, our data show a progressive synchronization of phasic excitation and inhibition during the course of ripples. Together, our results demonstrate the presence of phasic excitation during ripples reflecting an exquisite temporal coordination of assemblies of active pyramidal cells.