Extracellular Calcium Controls the Expression of Two Different Forms of Ripple-Like Hippocampal Oscillations

Abstract

Hippocampal high-frequency oscillations (HFOs) are prominent in physiological and pathological conditions. During physiological ripples (100 -200 Hz), few pyramidal cells fire together coordinated by rhythmic inhibitory potentials. In the epileptic hippocampus, fast ripples (Ͼ200 Hz) reflect population spikes (PSs) from clusters of bursting cells, but HFOs in the ripple and the fast ripple range are vastly intermixed. What is the meaning of this frequency range? What determines the expression of different HFOs? Here, we used different concentrations of Ca 2ϩ in a physiological range (1-3 mM) to record local field potentials and single cells in hippocampal slices from normal rats. Surprisingly, we found that this sole manipulation results in the emergence of two forms of HFOs reminiscent of ripples and fast ripples recorded in vivo from normal and epileptic rats, respectively. We scrutinized the cellular correlates and mechanisms underlying the emergence of these two forms of HFOs by combining multisite, single-cell and paired-cell recordings in slices prepared from a rat reporter line that facilitates identification of GABAergic cells. We found a major effect of extracellular Ca 2ϩ in modulating intrinsic excitability and disynaptic inhibition, two critical factors shaping network dynamics. Moreover, locally modulating the extracellular Ca 2ϩ concentration in an in vivo environment had a similar effect on disynaptic inhibition, pyramidal cell excitability, and ripple dynamics. Therefore, the HFO frequency band reflects a range of firing dynamics of hippocampal networks.

Excitation and Inhibition Compete to Control Spiking during Hippocampal Ripples: Intracellular Study in Behaving Mice

“…Meanwhile, Ca 2ϩ regulates synaptic release and numerous other functions. Ca 2ϩ , like other divalent cations, also modulates disynaptic transmission by affecting spike threshold, which has recently been shown to modulate in vitro ripples (Aivar et al, 2014). Thus, an important goal of the present study was to compare ripples observed in in vitro slice experiments with ripples in the intact drug-free brain.…”

“…Intracellularly recorded action potentials in the drug-free intact animal offered the opportunity to test the hypothesis that spikes during ripples invade the soma antidromically from the postulated gap junction-connected axonal nets (Schmitz et al, 2001;Bähner et al, 2011;. Action potential waveforms during ripples and outside ripples (excluding burst spikes) were both found to be orthodromic ( Fig.…”

“…This model is primarily supported by in vitro slice experiments, including the demonstration of antidromic spikes recorded intracellularly in pyramidal cells during ripples in vitro (Papatheodoropoulos, 2008;Bähner et al, 2011), and the observation that gap junction blockers abolish ripples in vitro (Draguhn et al, 1998;Schmitz et al, 2001; and in vivo (Ylinen et al, 1995). Competing models require inhibition and interactions between excitation and inhibition (Buzsáki et al, 1992;Whittington et al, 1995;Ylinen et al, 1995;Traub et al, 1996;Brunel and Wang, 2003;Geisler et al, 2005;Rácz et al, 2009;Taxidis et al, 2012;Varga et al, 2012;Hájos et al, 2013;Chiovini et al, 2014;Karló cai et al, 2014).…”

Generation of physiological and pathological high frequency oscillations: the role of perisomatic inhibition in sharp-wave ripple and interictal spike generation

“…This moment was also marked by the onset of HFOs in the LFP; 4) compared to the SWR-generating state, the cellular excitability increased and excitatory transmission was enhanced, whereas inhibitory transmission (both somatic and dendritic) was compromised; 5) additionally, a strong short-term depression was also observed in the PVBC to PC transmission. Aivar et al (201 4) [64] induced similar transitions from healthy to pathological forms of ripples by decreasing [Ca2+]e. They found similar shifts in excitability parameters and transmission parameters and concluded, similarly, that failure of inhibition results in strong PC firing that shapes the fRIPs. The importance of PVBCs in seizure propagation has been recently demonstrated [65].…”

“…These findings explain Bragin et al's [1 6] original observation and support the consensus on RIP and fRIP generation [5, 8,[52][53][54] by showing that the LFP is dominated by inhibitory synaptic currents during SWRs [61 ] and by PC action potentials during IISs [60]. When inhibition fails during IIS, the balance is tipped in the same direction by the two counteracting mechanisms; on one side, the inhibitory synaptic currents disappear, while on the other side pyramidal cells start to fire en mass and the population spikes of their APs form the LFP signal of fast ripples (see also [64] fig 9). Fast ripples thus appear when and where inhibitory control is lost and massive PC firing erupts [71 ].…”