Phase-Locked Inhibition, but Not Excitation, Underlies Hippocampal Ripple Oscillations in Awake Mice In Vivo

Abstract

SummarySharp wave-ripple (SWR) oscillations play a key role in memory consolidation during non-rapid eye movement sleep, immobility, and consummatory behavior. However, whether temporally modulated synaptic excitation or inhibition underlies the ripples is controversial. To address this question, we performed simultaneous recordings of excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) and local field potentials (LFPs) in the CA1 region of awake mice in vivo. During SWRs, inhibition dominated over excitation, with a peak conductance ratio of 4.1 ± 0.5. Furthermore, the amplitude of SWR-associated IPSCs was positively correlated with SWR magnitude, whereas that of EPSCs was not. Finally, phase analysis indicated that IPSCs were phase-locked to individual ripple cycles, whereas EPSCs were uniformly distributed in phase space. Optogenetic inhibition indicated that PV+ interneurons provided a major contribution to SWR-associated IPSCs. Thus, phasic inhibition, but not excitation, shapes SWR oscillations in the hippocampal CA1 region in vivo.

Cation-chloride cotransporters and the polarity of GABA signaling in mouse hippocampal parvalbumin interneurons

“…Thus, KCC2 knockdown in cortical PCs was shown to also profoundly perturb neuronal excitability as well as network activity (Kelley et al , 2018; Goutierre et al , 2019). Since PV INs exert a critical control over the activity of cortical PCs (Pouille & Scanziani, 2001) and shape their rhythmic activities (Klausberger & Somogyi, 2008; Amilhon et al , 2015; Gan et al , 2017), altered CCC expression in these cells would be expected to profoundly perturb cortical rhythmogenesis. As most studies on CCC expression in the pathology lacked cell-subtype resolution, whether and how it is affected in PV INs remains to be fully explored and the consequences on cortical activity should then be further investigated.…”

“…In particular, parvalbumin-expressing interneurons (PV INs), which receive excitatory inputs from both local and distant PCs, in turn provide them with fast perisomatic inhibition (Hu et al , 2014). Fast inhibitory signaling by PV INs controls the timing of principal cell activity (Pouille & Scanziani, 2001) and plays a major role in the generation of rhythmic activities (Klausberger & Somogyi, 2008; Amilhon et al , 2015; Gan et al , 2017) as well as the segregation of PCs into functional assemblies (Agetsuma et al , 2018). However, in addition to excitatory inputs from PCs, PV INs also receive GABAergic innervation from local interneurons (Chamberland & Topolnik, 2012), including some specialized in interneuron inhibition (Gulyas et al , 1996), as well as long-range projecting interneurons (Freund & Antal, 1988).…”

Defining the synaptic mechanisms that tune CA3-CA1 reactivation during sharp-wave ripples

“…The biophysical model of CA3-CA1 SWR activity which we propose in this study builds on an extensive literature on the mechanisms of ripples and sharp waves. In vitro and in vivo studies have shown that in CA1 ripples are dominated by inhibitory phasic activity (Gan et al 2017; Schlingloff et al 2014), and basket cells spike at high frequency (Schlingloff et al 2014; Varga et al 2012) in localized groups (Patel et al 2013). Meanwhile, pyramidal cells spike relatively rarely, phase-locked to windows of opportunity left by the ongoing oscillatory inhibitory signal (Csicsvari et al 1999a; b).…”

Balanced synaptic currents underlie low‐frequency oscillations in the subiculum

“…Balanced excitation–inhibition (E/I) during activity is a common feature of neuronal networks (Anderson, Carandini, & Ferster, ; Haider, Duque, Hasenstaub, & McCormick, ; Okun & Lampl, ; Rudolph, Pospischil, Timofeev, & Destexhe, ). During evoked activity and local field potential (LFP) oscillations, balanced E/I currents underlie depolarizations in hippocampal and cortical excitatory principal cells in vivo (Atallah & Scanziani, ; Gan, Weng, Pernía‐Andrade, Csicsvari, & Jonas, ; Wilent & Contreras, ). A key characteristic of balanced E/I inputs is that they maintain membrane voltage near spike threshold and permit precise control over spike output rate (Gabernet, Jadhav, Feldman, Carandini, & Scanziani, ; Higley & Contreras, ; Shu, Hasenstaub, & McCormick, ; Wehr & Zador, ).…”

“…Additionally, recruitment of inhibition over a range of network activity levels likely prevents runaway excitation in networks with strong recurrent connections such as the subiculum (Drexel et al, ; Harris, Witter, Weinstein, & Stewart, ). In the hippocampus, fast frequency oscillations such as gamma (30–80 Hz) and ripples (~200 Hz) have been shown to have properties consistent with generation through correlated and balanced synaptic currents (Atallah & Scanziani, ; English et al, ; Gan et al, ). For lower frequencies such as theta (3–12 Hz), however, balanced network activity has not been recognized as a potentially contributing factor to this oscillation range.…”