Ripple activity in the dentate gyrus of dishinibited hippocampus-entorhinal cortex slices

Abstract

Fast oscillations at approximately 200 Hz, termed ripples, occur in the hippocampus and cortex of several species, including humans, and are thought to play a role in physiological (e.g., sensory information processing or memory consolidation) and pathological (e.g., seizures) processes. Blocking gamma-aminobutyric acid type A (GABA(A)) receptor-mediated inhibition represents one of the most often used models of epileptiform discharge. Here we found that bath application of the GABA(A) receptor antagonist picrotoxin (50 microM) to mouse hippocampus-entorhinal cortex slices induced spontaneous epileptiform activity (duration 536.6 +/- 146.1 msec, mean +/- SD; interval of occurrence 14.8 +/- 3.3 sec, n = 12) with two distinct phases of discharge; the first was characterized, in the dentate gyrus only, by high-frequency, field oscillations (ripples) at 206.3 +/- 23.4 Hz (n = 12), whereas the second component corresponded to afterdischarges in the theta range frequency. Ripples, which were also recorded in "minislices" only of the dentate gyrus, were unaffected by application of the mu-opioid receptor agonist (D-Ala2-N-Me-Phe,Gly-ol)enkephalin (10 microM; n = 6) or the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxy-piperazine-4-yl)-propyl-l-phosphonate (10 microM; n = 5). In contrast, the non-NMDA glutamatergic receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione (10 microM; n = 5) completely blocked all picrotoxin-induced activities. In addition, application of the GABA(B) receptor agonist baclofen (0.01-0.5 microM; n = 6) dose dependently and reversibly abolished all picrotoxin-induced activities. We also found that application of the gap-junction decouplers carbenoxolone (0.2-0.5 mM; n = 6) or octanol (0.2-0.5 mM; n = 3) blocked the second phase while leaving ripples unchanged. These findings demonstrate that the disinhibited dentate gyrus can generate ripple activity at approximately 200 Hz that is contributed by ionotropic glutamatergic mechanisms and is not dependent on either GABA(A) receptor-mediated or gap-junction mechanisms.

Mechanisms of physiological and epileptic HFO generation

“…Whether HFOs induced acutely in brain tissue model epilepsy-related pHFO or physiological sharp wave ripples is an open question (Taxidis et al, 2011;Ylinen et al, 1995). Evidence from the dentate gyrus exposed to the convulsant drug picrotoxin (D'Antuono et al, 2005), argues against a role for inhibitory synapses which contrasts with the evidence for physiological ripples in the same area in vivo (Ylinen et al, 1995) and reinforces the point that oscillations in the same frequency band are not necessarily the same phenomenon. In some studies loss of inhibition resulted in a transformation of sharp wave ripples, with HFO in the ripple band, to epileptiform discharges, with superimposed fast ripples, suggesting a role of inhibition in ripples and not fast ripples (Behrens et al, 2007).…”

“…In some studies loss of inhibition resulted in a transformation of sharp wave ripples, with HFO in the ripple band, to epileptiform discharges, with superimposed fast ripples, suggesting a role of inhibition in ripples and not fast ripples (Behrens et al, 2007). Evidence on roles for gap junctions in HFOs is both negative (D'Antuono et al, 2005) and positive (Nimmrich et al, 2005). A study of CA3 in elevated extracellular K + argues for a role for intrinsic burst firing characteristic of CA3 pyramidal cells (Dzhala and Staley, 2004).…”

“…However, a poor correlation between the firing frequency of individual cells and the dominant spectral peak in the local EEG confirms that fast ripples emerge as a network phenomenon and that single cells rarely fire faster than 400 Hz. This leads to the out-ofphase cluster hypothesis that suggest that independent pools of cells fire in concert but outof-phase with each other thus contributing to the higher frequency of fast ripples (Bikson et al, 2003a;D'Antuono et al, 2005;Foffani et al, 2007;Ibarz et al, 2010;Jiruska et al, 2010a).…”

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…Moreover, experiments performed in both in vitro and in vivo preparations indicate that fast ripples do not depend on inhibitory transmission as they are easily observed during GABA A receptor blockade and, indeed, they appear to represent the synchronous firing of principal (glutamatergic) neurons (D'Antuono et al, 2005;Engel et al, 2009;Bragin et al, 2011). The possibility that fast ripples emerge as the result of loss of synchronization during jittery, out-of-phase burst firing of principal cells in the epileptic hippocampus has been proposed (Foffani et al, 2007;Ibarz et al, 2010).…”

Short-Duration Epileptic Discharges Show a Distinct Phase Preference During Ongoing Hippocampal Slow Oscillations

“…Because penicillin generates epileptiform ac- tivity through GABA A receptor antagonism (Dichter and Spencer 1969a,b), the resultant network activity presumably reflects a disinhibited hippocampal network. As such, a reduced level of network inhibition can generate abnormal high-frequency oscillatory activity in the DG and the entorhinal cortex, an event that is limited to epileptic conditions D'Antuono et al 2005;de Guzman et al 2008;Staba et al 2002). Thus penicillin may facilitate pathological network interactions that are similar to those observed in the epileptic HPC.…”