NAD(P)H Fluorescence Transients after Synaptic Activity in Brain Slices: Predominant Role of Mitochondrial Function

Brennan, Angela; Connor, John A.; Shuttleworth, C. William

doi:10.1038/sj.jcbfm.9600292

Cited by 93 publications

(127 citation statements)

References 53 publications

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“…The decrease in basal NADH fluorescence during hypoglycemia reflects a reduction in the potential for ATP regeneration but in the presence of normal oxygen levels, in effect forcing most of the NADH to NAD. Brennan et al demonstrated that an adenosine A1 receptor antagonist could alleviate 2-deoxyglucose (chemical hypoglycemia) induced attenuation of the biphasic NADH response to a stimulus train [5]. We also found that glucose concentrations modulate the second phase of the NADH biphasic response, which may reflect impaired recovery of mitochondrial energy intermediates in the lowered glucose media [25,39].…”

Section: Nadh Measurementssupporting

confidence: 62%

Effects of relative hypoglycemia on LTP and NADH imaging in rat hippocampal slices

2007

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Cognitive and neuronal impairment in diabetes may be associated with iatrogenic hypoglycemia, particularly at low serum glucose levels (< 3 mM). To evaluate cellular impairment, we assessed acute hippocampal slice functioning during decreased ambient glucose, by monitoring evoked field excitatory post-synaptic potentials (fEPSP), and slice nicotinamide adenine dinucleotide (NADH) fluorescence. The effects of lowered glucose levels (60 min) were analyzed by examining the induction and maintenance of long-term potentiation (LTP), and NADH metabolic imaging in the CA1 region. The basal fEPSP response was reduced by lowered ambient glucose, an effect that was reversible in 2.5 mM glucose, partially reversible in 1.25 mM glucose and irreversible in 0 mM glucose, after 25 min recovery. LTP induction and maintenance declined during glucose restriction, demonstrating reversibly failed maintenance in 5 mM and 2.5 mM ambient glucose, and absent induction in 1.25 mM glucose. Peak NADH levels observed during train-induced biphasic transients were significantly reduced during 1.25 mM and 2.5 mM glucose. Significant functional compromise in our slice model occurred at 2.5 mM ambient glucose, equivalent to <1mM tissue glucose in the slice center, due to diffusion limitations and active glucose utilization. This tissue glucose level correlates with human observations of a serum threshold of <3mM for cognitive impairment, since brain tissue glucose is approximately one third of serum levels. The physiological effects of hypoglycemia in our slice model, assessed through fEPSP, LTP, and NADH responses, replicate closely the in vivo situation, confirming the usefulness of this model in assessing consequences of relative hypoglycemia.

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Section: Nadh Measurementssupporting

confidence: 62%

Effects of relative hypoglycemia on LTP and NADH imaging in rat hippocampal slices

2007

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“…[38][39][40][41] This in vitro preparation also provides a reasonable model for examining energy metabolism during different forms of neuronal network activation. [42][43][44][45] In the hippocampal slices, persistent gamma oscillations can be reliably induced by bath application of cholinergic or glutamatergic receptor agonists at nanomolar to low micromolar concentrations ( Figures 1A and 1B). The most widespread models use acetylcholine or carbachol for activation of metabotropic cholinergic receptors, or kainate (kainic acid) for activation of ionotropic glutamatergic receptors.…”

Section: Gamma Oscillations and Cortical Information Processingmentioning

confidence: 99%

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

Kann

Papageorgiou

Draguhn

2014

J Cereb Blood Flow Metab

211

227

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Gamma oscillations (B30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency ('fast-spiking') and synchronize the activity of numerous pyramidal cells by rhythmic inhibition ('clockwork'). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and g-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited ('interneuron energy hypothesis'). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia.

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“…10,11 We applied pharmacology to dissect single components contributing to the enhanced energy consumption. Figures 3A--3E, n ¼ 5, 13, 13).…”

Section: Energy Demand Associated With Pre-and Postsynaptic Ion Fluxesmentioning

confidence: 99%

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

Liotta

Rösner

Huchzermeyer

et al. 2012

J Cereb Blood Flow Metab

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Neuroenergetic models of synaptic transmission predicted that energy demand is highest for action potentials (APs) and postsynaptic ion fluxes, whereas the presynaptic contribution is rather small. Here, we addressed the question of energy consumption at Schaffer-collateral synapses. We monitored stimulus-induced changes in extracellular potassium, sodium, and calcium concentration while recording partial oxygen pressure (pO 2 ) and NAD(P)H fluorescence. Blockade of postsynaptic receptors reduced ion fluxes as well as pO 2 and NAD(P)H transients by B50%. Additional blockade of transmitter release further reduced Na þ , K þ , and pO 2 transients by B30% without altering presynaptic APs, indicating considerable contribution of Ca 2 þ -removal, transmitter and vesicle turnover to energy consumption. Keywords: action potential; brain slice; electrophysiology; energy metabolism; evoked potentials; hippocampus INTRODUCTION Energy limitations determine the computational power and speed of neuronal systems. 1 Therefore, it is of critical importance to identify the energy demand associated with processes involved in neuronal computing such as synaptic transmission and action potential (AP) firing. Theoretical calculations on the basis of current kinetics in squid giant axons suggested that APs and postsynaptic ion fluxes rather than presynaptic processes determine energy consumption. 1,2 More recently, energy efficient AP generation and conduction was described in hippocampal mossy fibers. 3--5 Recalculating the energy need for APs suggests larger contribution of postsynaptic and presynaptic processes and transmitter uptake to the energy demand of synaptic transmission. 6,7 The authors predicted that in cerebral cortex, 50% of signaling associated energy is spent on restoration of ion fluxes at postsynaptic glutamate receptors, 21% is spent on APs, 20% on resting potentials, 5% and 4% on presynaptic transmitter release and transmitter recycling, respectively. However, such numbers have to be calculated or determined experimentally for each brain area in question as synaptic densities, receptor types, and ion channel expression differ for each particular signaling pathway. Journal of Cerebral BloodHere, we sought to determine the contribution of pre-and postsynaptic processes to changes in energy metabolism associated with glutamatergic and GABAergic transmission at the hippocampal Schaffer-collateral synapse that represents one of the best-studied connections in the archicortex. We monitored stimulus-induced changes in extracellular potassium, sodium, and calcium concentrations ([K þ ] o , [Na þ ] o , [Ca 2 þ ] o ) while recording tissue partial oxygen pressure (pO 2 ) and metabolism-related NAD(P)H transients. The energy demand of each single component of synaptic transmission

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NAD(P)H Fluorescence Transients after Synaptic Activity in Brain Slices: Predominant Role of Mitochondrial Function

Cited by 93 publications

References 53 publications

Effects of relative hypoglycemia on LTP and NADH imaging in rat hippocampal slices

Effects of relative hypoglycemia on LTP and NADH imaging in rat hippocampal slices

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

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

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