Replay of neuronal activity during hippocampal sharp wave-ripples (SWRs) is essential
in memory formation. To understand the mechanisms underlying the initiation of irregularly
occurring SWRs and the generation of periodic ripples, we selectively manipulated
different components of the CA3 network in mouse hippocampal slices. We recorded EPSCs
and IPSCs to examine the buildup of neuronal activity preceding SWRs and analyzed
the distribution of time intervals between subsequent SWR events. Our results suggest
that SWRs are initiated through a combined refractory and stochastic mechanism. SWRs
initiate when firing in a set of spontaneously active pyramidal cells triggers a gradual,
exponential buildup of activity in the recurrent CA3 network. We showed that this
tonic excitatory envelope drives reciprocally connected parvalbumin-positive basket
cells, which start ripple-frequency spiking that is phase-locked through reciprocal
inhibition. The synchronized GABAA receptor-mediated currents give rise to a major
component of the ripple-frequency oscillation in the local field potential and organize
the phase-locked spiking of pyramidal cells. Optogenetic stimulation of parvalbumin-positive
cells evoked full SWRs and EPSC sequences in pyramidal cells. Even with excitation
blocked, tonic driving of parvalbumin-positive cells evoked ripple oscillations. Conversely,
optogenetic silencing of parvalbumin-positive cells interrupted the SWRs or inhibited
their occurrence. Local drug applications and modeling experiments confirmed that
the activity of parvalbumin-positive perisomatic inhibitory neurons is both necessary
and sufficient for ripple-frequency current and rhythm generation. These interneurons
are thus essential in organizing pyramidal cell activity not only during gamma oscillation,
but, in a different configuration, during SWRs.
