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Modeling of Metabolic and Electrophysiological Processes in Neuronal Cells

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Oxygen consumption rates in brain slices

Depth profiles of partial oxygen pressure (pO2) during three different activity states. (A) Representative sample traces of pO2 depth profiles in the absence of spiking (TTX, black trace), spontaneous network activity (SPON, dark gray trace), and cholinergically induced gamma oscillations (GAM, light gray trace). (B) Quantification of lowest pO2 values as determined during the three different activity states. (C) Quantification of oxygen consumption rate in the different activity states.

The brain is an organ with a high metabolic capacity, adapting energy utilization during different activity states of neuronal networks. To quantify energetic demand, we addressed this issue in area CA3 of hippocampal slice cultures under well-defined recording conditions using a 20% O2 gas mixture. We combined recordings of local field potential and interstitial partial oxygen pressure (pO2) during three different activity states, namely fast network oscillations in the gamma frequency band (30 to 100 Hz), spontaneous network activity, and absence of spiking (action potentials). Oxygen consumption rates were determined by pO2 depth profiles with high spatial resolution and a mathematical model that considers convective transport, diffusion, and activity-dependent consumption of oxygen. We show that: (1) Relative oxygen consumption rate during cholinergic gamma oscillations was 2.2-fold and 5.3-fold higher compared with spontaneous activity and absence of spiking, respectively. (2) Gamma oscillations were associated with a similarly large decrease in pO2 as observed previously with a 95% O2 gas mixture. (3) Sufficient oxygenation during fast network oscillations in vivo is ensured by the calculated critical radius of 30 to 40 mm around a capillary. We conclude that the structural and biophysical features of brain tissue permit variations in local oxygen consumption by a factor of about five [1].

Publications:

  1. Huchzermeyer C*, Berndt N*, Holzhütter HG*, Kann O*. Oxygen consumption rates during three different neuronal activity states in the hippocampal CA3 network. J Cereb Blood Flow Metab. 2013 Feb;33(2):263-71.

Project funding: Collaborative Research Center for "Theoretical Biology: Robustness, Modularity and Evolutionary Design of Living Systems" SFB 618 (grant no. 5485271) sponsored by the DFG (German Research Foundation).

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How NAD(P)H fluorescence mirrors neuronal energy metabolism

(A) Reactions and transport processes included in the single-cell kinetic model. (B) Schematic representation of the slice model used to simulate spatial oxygen gradients within a brain slice. (C) Schematic representation of the tissue model used to simulate in vivo NADH transients.

Imaging of the cellular fluorescence of the reduced form of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) is one of the few metabolic readouts that enable noninvasive and time-resolved monitoring of the functional status of mitochondria in neuronal tissues. Stimulation-induced transient changes in NAD(P)H fluorescence intensity frequently display a biphasic characteristic that is influenced by various molecular processes, e.g., intracellular calcium dynamics, tricarboxylic acid cycle activity, the malate–aspartate shuttle, the glycerol-3-phosphate shuttle, oxygen supply or ATP demand. To evaluate the relative impact of these processes, we developed and validated a detailed physiologic mathematical model of the energy metabolism of neuronal cells and used the model to simulate metabolic changes of single cells and tissue slices under different settings of stimulus-induced activity and varying nutritional supply of glucose, pyruvate or lactate [1]. Our computational approach reconciles different and sometimes even controversial experimental findings and improves our mechanistic understanding of the metabolic changes underlying live-cell NAD(P)H fluorescence transients. In subsequent studies, we investigated the energy metabolism underlying cortical information processing [2]. We concluded that gamma oscillations featuring high energetics require a hemodynamic response to match the oxygen consumption of respiring mitochondria and that perisomatic inhibition significantly contributes to the brain energy budget. Our data show that energy expenditure is strongly dependent on the neuronal network activity state and may reach critical levels during higher brain functions.

We also used these models to assess changes in energy metabolism in different physiological and pathological situations, like neurodegeneration, epilepsy, demyelination disease, or anesthesia (see the other project descripts).

Publications:

  1. Berndt N, Kann O, Holzhütter HG. Physiology-based kinetic modeling of neuronal energy metabolism unravels the molecular basis of temporal NAD(P)H fluorescence profiles. J Cereb Blood Flow Metab. 2015 Sep;35(9):1494-506.
  2. Schneider J*, Berndt N*, Papageorgiou IE, Maurer J, Bulik S, Both M, Draguhn A, Holzhütter HG, Kann O. Local oxygen homeostasis during various neuronal network activity states in the mouse hippocampus. J Cereb Blood Flow Metab. 2019 May;39(5):859-873.

Project funding: The projects were in part funded by the DFG grant no. 650953 and 408355133 and the German Systems Biology Program “Virtual Liver” (grant no. 0315741) sponsored by the German Federal Ministry of Education and Research (BMBF) and by the German Research Foundation (DFG) within the Collaborative Research Center (SFB) 1134.

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Metabolic alterations in neurodegenerative diseases

Schematic of the mathematical model of mitochondrial energy metabolism.

Steadily growing experimental evidence suggests that mitochondrial dysfunction plays a key role in the age-dependent impairment of nerve cells underlying several neurodegenerative diseases. Especially, reduced activity of brain α-ketoglutarate dehydrogenase complex (KGDHC), reduced activity of complex I of the respiratory chain (RC), and increased reactive oxygen species (ROS) production occur in several neurodegenerative diseases like Parkinson's disease and Alzheimer's disease. To understand the metabolic regulation underlying these experimental findings we developed and applied a detailed kinetic model of mitochondrial energy metabolism. Model simulations revealed a threshold-like decline of the ATP production rate at about 60% inhibition of KGDHC accompanied by a significant increase of the mitochondrial membrane potential. We also showed that the reduction state of those sites of the respiratory chain proposed to be involved in ROS production decreased with increasing degree of KGDHC inhibition suggesting a ROS-reducing effect of KGDHC inhibition [1].

Next, we applied the model to a situation where both KGDHC and complex I exhibit reduced activities. These calculations reveal synergistic effects concerning the energy metabolism but antagonistic effects concerning ROS formation: the drop in the ATP production capacity is more pronounced than at inhibition of either enzyme complex alone. Interestingly, however, the reduction state of the ROS-generating sites of the impaired complex I becomes significantly lowered if additionally the activity of the KGDHC is reduced [2].

Publications:

  1. Berndt N, Bulik S, Holzhütter HG. Kinetic Modeling of the Mitochondrial Energy Metabolism of Neuronal Cells: The Impact of Reduced α-Ketoglutarate Dehydrogenase Activities on ATP Production and Generation of Reactive Oxygen Species. Int J Cell Biol. 2012;2012:757594.
  2. Berndt N, Holzhütter HG, Bulik S. Implications of enzyme deficiencies on mitochondrial energy metabolism and reactive oxygen species formation of neurons involved in rotenone-induced Parkinson's disease: a model-based analysis. FEBS J. 2013 Oct;280(20):5080-93.

Project funding: The project was in part funded by the German Systems Biology Program “Virtual Liver” (grant no. 0315741) sponsored by the German Federal Ministry of Education and Research (BMBF).

Cooperation partner: Hermann-Georg Holzhütter (Charité, Institute of Biochemistry, Computational Systems Biochemistry Group)

Impact of anesthetics on cerebral energy metabolism during light and deep anesthesia

Illustration of the effects of propofol on neuronal functionality during and after anesthesia.

General anesthesia is a drug-induced, reversible state of unconsciousness, amnesia, analgesia, and akinesia. The cortical electroencephalogram displays typical dose-dependent changes during anesthesia with characteristic stages of neuronal activity. Despite indisputable improvements in anesthesiology, major concerns related to the long-term effects of anesthetics on the central nervous system are rising. Specifically, deep anesthesia has been associated with postoperative delirium, long-lasting postoperative cognitive dysfunction, and increased mortality. The underlying role of anesthetics in these neurological complications remains unclear and needs urgent clarification.

Propofol is the most frequently used intravenous anesthetic for induction and maintenance of anesthesia acting primarily as a GABAA-agonist, but effects on other neuronal receptors and voltage-gated ion channels have been described. Besides its direct effect on neurotransmission, propofol-dependent impairment of mitochondrial function in neurons has been suggested to be responsible for neurotoxicity and postoperative brain dysfunction. To clarify the potential neurotoxic effect in more detail, we investigated the effects of propofol on neuronal energy metabolism of hippocampal slices of the stratum pyramidale of area CA3 at different activity states [1]. We combined oxygen measurements, electrophysiology, and Flavin adenine dinucleotide (FAD)-imaging with computational modeling to uncover molecular targets in mitochondrial energy metabolism that are directly inhibited by propofol. We found that high concentrations of propofol (100 μM) significantly decrease population spikes, paired-pulse ratio, the cerebral metabolic rate of oxygen consumption (CMRO2), frequency and power of gamma oscillations and increase FAD-oxidation. Model-based simulation of mitochondrial FAD redox state at inhibition of different respiratory chain (RC) complexes and the pyruvate-dehydrogenase show that the alterations in FAD autofluorescence during propofol administration can be explained with a strong direct inhibition of the complex II (cxII) of the RC. While this inhibition may not affect ATP availability under normal conditions, it may have an impact on high energy demand. Our data support the notion that propofol may lead to neurotoxicity and neuronal dysfunction by directly affecting the energy metabolism in neurons.

In recent studies, we also investigated the effect of the anesthetics isoflurane and sevoflurane on neuronal transmission and metabolism in Wistar rats and brain slice preparations [2, 3].

Publications:

  1. Berndt N, Rösner J, Haq RU, Kann O, Kovács R, Holzhütter HG, Spies C, Liotta A. Possible neurotoxicity of the anesthetic propofol: evidence for the inhibition of complex II of the respiratory chain in area CA3 of rat hippocampal slices. Arch Toxicol. 2018 Oct;92(10):3191-3205.
  2. Berndt N, Kovács R, Schoknecht K, Rösner J, Reiffurth C, Maechler M, Holzhütter HG, Dreier JP, Spies C, Liotta A. Low neuronal metabolism during isoflurane-induced burst suppression is related to synaptic inhibition while neurovascular coupling and mitochondrial function remain intact. J Cereb Blood Flow Metab. 2021 Apr 25;271678X211010353.
  3. Maechler M, Rösner J, Wallach I, Geiger JRP, Spies C, Liotta A*, Berndt N*. Sevoflurane Effects on Neuronal Energy Metabolism Correlate with Activity States while Mitochondrial Function Remains Intact. Int J Mol Sci. 2022 Mar 11;23(6):3037.

Project funding: This work is in part funded by the DFG grant no. 650953 and 408355133 as well as the German Systems Biology Program "LiSyM" (grant no. 31L0057) sponsored by the German Federal Ministry of Education and Research (BMBF). Agustin Liotta is participant in the BIH Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health.

Cooperation partners: