Hippocampal ripples are involved in memory consolidation, but the mechanisms underlying their generation remain unclear. Models relying on interneuron networks in the CA1 region disagree on the predominant source of excitation to interneurons: either "direct," via the Schaffer collaterals that provide feedforward input from CA3 to CA1, or "indirect," via the local pyramidal cells in CA1, which are embedded in a recurrent excitatory-inhibitory network. Here, we used physiologically constrained computational models of basket-cell networks to investigate how they respond to different conditions of transient, noisy excitation. We found that direct excitation of interneurons could evoke ripples (140-220 Hz) that exhibited intraripple frequency accommodation and were frequency-insensitive to GABA modulators, as previously shown in experiments. In addition, the indirect excitation of the basket-cell network enabled the expression of intraripple frequency accommodation in the fast-gamma range (90-140 Hz), as In our model, intraripple frequency accommodation results from a hysteresis phenomenon in which the frequency responds differentially to the rising and descending phases of the transient excitation. Such a phenomenon predicts a maximum oscillation frequency occurring several milliseconds before the peak of excitation. We confirmed this prediction for ripples in brain slices from male mice. These results suggest that ripple and fast-gamma episodes are produced by the same interneuron network that is recruited via different excitatory input pathways, which could be supported by the previously reported intralaminar connectivity bias between basket cells and functionally distinct subpopulations of pyramidal cells in CA1. Together, our findings unify competing inhibition-first models of rhythm generation in the hippocampus. The hippocampus is a part of the brain of humans and other mammals that is critical for the acquisition and consolidation of memories. During deep sleep and resting periods, the hippocampus generates high-frequency (∼200 Hz) oscillations called ripples, which are important for memory consolidation. The mechanisms underlying ripple generation are not well understood. A prominent hypothesis holds that the ripples are generated by local recurrent networks of inhibitory neurons. Using computational models and experiments in brain slices from rodents, we show that the dynamics of interneuron networks clarify several previously unexplained characteristics of ripple oscillations, which advances our understanding of hippocampus-dependent memory consolidation.

The entorhinal cortices in the temporal lobe of the brain are key structures relaying memory related information between the neocortex and the hippocampus. The medial entorhinal cortex (MEC) routes spatial information, whereas the lateral entorhinal cortex (LEC) routes predominantly olfactory information to the hippocampus. Gamma oscillations are known to coordinate information transfer between brain regions by precisely timing population activity of neuronal ensembles. Here, we studied the organization of in vitro gamma oscillations in the MEC and LEC of the transgenic (tg) amyloid precursor protein (APP)-presenilin 1 (PS1) mouse model of Alzheimer’s Disease (AD) at 4–5 months of age. In vitro gamma oscillations using the kainate model peaked between 30–50 Hz and therefore we analyzed the oscillatory properties in the 20–60 Hz range. Our results indicate that the LEC shows clear alterations in frequency and power of gamma oscillations at an early stage of AD as compared to the MEC. The gamma-frequency oscillation slows down in the LEC and also the gamma power in dorsal LEC is decreased as early as 4–5 months in the tg APP-PS1 mice. The results of this study suggest that the timing of olfactory inputs from LEC to the hippocampus might be affected at an early stage of AD, resulting in a possible erroneous integration of the information carried by the two input pathways to the hippocampal subfields.

Sharp wave-associated ∼200-Hz ripple oscillations in the hippocampus have been implicated in the consolidation of memories. However, knowledge on mechanisms underlying ripples is still scarce, in particular with respect to synaptic involvement of specific cell types. Here, we used cell-attached and whole-cell recordings in vitro to study activity of pyramidal cells and oriens-lacunosum-moleculare (O-LM) interneurons during ripples. O-LM cells received ripple-associated synaptic input that arrived delayed (3.3 ± 0.3 ms) with respect to the maximum amplitude of field ripples and was locked to the ascending phase of field oscillations (mean phase: 209 ± 6°). In line, O-LM cells episodically discharged late during ripples (∼6.5 ms after the ripple maximum), and firing was phase-locked to field oscillations (mean phase: 219 ± 9°). Our data unveil recruitment of O-LM neurons during ripples, suggesting a previously uncharacterized role of this cell type during sharp wave-associated activity.

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