J. Neurosci., 38: 3124-3146, 2018.
DOI: 10.1523/JNEUROSCI.0118-17.2018
See also the associated Journal Club Article ``Feedback and Feedforward Inhibition May Resonate
Distinctly in the Ripple Symphony''
by Sanchez-Aguilera, Navas-Olive, and Valero.
J. Donoso, D. Schmitz, N. Maier*, R. Kempter*
*co-last authors
Abstract
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
intra-ripple frequency accommodation (IFA) and were
frequency-insensitive to GABA modulators, as previously shown in
in-vitro experiments. In addition, the indirect excitation of the
basket-cell network enabled the expression of IFA in the fast-gamma
range (90-140 Hz), as in vivo. In our model, IFA 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. Taken together, our
findings unify competing inhibition-first models of rhythm
generation in the hippocampus.
Significance Statement
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 Hertz) 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.