Gamma Oscillations and Spontaneous Network Activity in the Hippocampus Are Highly Sensitive to Decreases in pO₂and Concomitant Changes in Mitochondrial Redox State

Abstract

Gamma oscillations have been implicated in higher cognitive processes and might critically depend on proper mitochondrial function. Using electrophysiology, oxygen sensor microelectrode, and imaging techniques, we investigated the interactions of neuronal activity, interstitial pO 2 , and mitochondrial redox state [NAD(P)H and FAD (flavin adenine dinucleotide) fluorescence] in the CA3 subfield of organotypic hippocampal slice cultures. We find that gamma oscillations and spontaneous network activity decrease significantly at pO 2 levels that do not affect neuronal population responses as elicited by moderate electrical stimuli. Moreover, pO 2 and mitochondrial redox states are tightly coupled, and electrical stimuli reveal transient alterations of redox responses when pO 2 decreases within the normoxic range. Finally, evoked redox responses are distinct in somatic and synaptic neuronal compartments and show different sensitivity to changes in pO 2 . We conclude that the threshold of interstitial pO 2 for robust CA3 network activities and required mitochondrial function is clearly above the "critical" value, which causes spreading depression as a result of generalized energy failure. Our study highlights the importance of a functional understanding of mitochondria and their implications on activities of individual neurons and neuronal networks.

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

“…74,121 Similar observations have been made in interneuron subpopulations of the visual cortex. 124,125 We note that these findings High energy utilization 41,57,63,64,67 Exquisite sensitivity to metabolic stress 41,44,47,163,164 AP, action potential. Some unique features of (A) fast-spiking, parvalbuminpositive interneurons and (B) gamma oscillations (30 to 100 Hz) are summarized, including a selection of key references.…”

“…163 Such decreases in gamma oscillation power were also observed in vitro during pharmacological interference with mitochondrial function ('poisoning'), namely inhibition of the mitochondrial respiratory chain by rotenone (acting on complex I) or potassium cyanide (acting on cytochrome c oxidase in complex IV), or after mitochondrial uncoupling by protonophores. 41,164,165 Intriguingly, other forms of activity such as electrical stimulus-evoked neuronal activation, low-frequency oscillations, and seizure-like events were much more resistant to low pO 2 or pharmacological inhibition of the mitochondrial respiratory chain in vitro and in vivo, 41,44,163 suggesting that fast-spiking interneurons that are crucial for the gamma oscillations were primarily affected.…”

“…133 Moderate metabolic stress may thus disrupt fast phasic inhibition of fastspiking interneurons more effectively than other types of inhibition or pyramidal cell excitation in neuronal networks 87,116 ( Figure 2B). The disruption of rhythmic inhibition would cause rapid loss of gamma oscillations, with devastating consequences on information processing in local and, perhaps, remote cortical networks 34,41,44,164 (Figure 3). This pathophysiological mechanism might help to explain the exceptional vulnerability of higher brain functions during acute metabolic stress, which has long been known from clinical medicine and experimental neurology.…”

Energy Demand of Synaptic Transmission at the Hippocampal Schaffer-Collateral Synapse

“…Changes in ion concentrations and pO 2 were calculated by using the modified Nernst equation and the pO 2 calibration curves. 8 Stimulus-induced fp responses were analyzed to monitor changes in presynaptic APs and postsysnaptic APs and EPSPs. The amplitude of the first, TTX-sensitive part (afferent volley) of the fp response was used to monitor changes in presynaptic APs, whereas the amplitude of the second, CNQX/DL-APV/MCPG/bicuculline-sensitive part of the fp response was used to determine changes in postsynaptic APs and field EPSPs ( Figures 1A--1D).…”

“…We have shown previously that the same ion movements and consequently the same amount of pump activity can induce different pO 2 transients depending on the absolute tissue pO 2 . 8 At high tissue pO 2 (95%) respiration might become partially uncoupled making exact calculation of ATP production per mM oxygen extremely difficult. 21 Nevertheless, our data indicate a considerable contribution of presynaptic processes to energy demand of synaptic transmission.…”