Bioenergetics of fast neuronal network oscillations
A neuron contains hundreds of mitochondria that produce most of the intracellular energy carrier, adenosine triphosphate (ATP) through the process of oxidative phosphorylation. ATP is essential for maintenance of ion gradients across neuronal membranes and, thus, for neuronal excitability and signalling. The goal of this project is to identify the energetic foundations and limitations of neuronal information processing. In particular, we study both features and bioenergetics of hippocampal gamma oscillations (30-100 Hz) that have been implicated in cognitive tasks such as perception, learning and memory. Disturbances of gamma oscillations that are caused by mitochondrial dysfunction and metabolic stress might be a key pathogenic factor for cognitive decline in various neurological and psychiatric disorders
Fig. 1: Neurons, mitochondria and gamma oscillations in slice cultures.
(A) DIC image of pyramidal cells (arrows) in stratum pyramidale of subfield CA3, where microelectrodes were placed to record, for example, changes in local field potential (panel C) and interstitial partial oxygen pressure (Figure 2).
(B) Overlay with fluorescence image of mitochondria-targeted indicator, rhodamine 123 (Rh-123). Note that pyramidal cells contain many individual mitochondria as well as small mitochondrial clusters, whereas Rh-123 fluorescence is absent in nuclei (asterisks). Scale bars denote 10 µm.
(C) Gamma oscillations in local field potentials (upper traces) were simultaneously recorded in subfields CA3 and CA1 (scheme). The auto-correlogram (auto) reveals a peak frequency of 33 Hz, the cross-correlogram (cross) a phase lag of 1.2 ms for oscillations in CA1 (with reference to CA3).
Fig 2: Oxygen consumption and mitochondrial complex I inhibition during gamma oscillations in slice cultures.
(A) Changes in interstitial partial oxygen pressure (pO2, trace) were recorded in the slice core of subfield CA3. Acetylcholine (5 µM) and physostigmine (1 µM) (upper light grey bar) were applied with the recording solution to elicit gamma oscillations (C).
(B) Histogram summarizing absolute values of pO2 during the six different conditions of the experiment (n = 7). Note the significant increase in oxygen consumption during gamma oscillations (conditions 2 and 3) and the rapid inhibition by application of selective mitochondrial complex I inhibitor, rotenone (1 µM) (conditions 4-6; lower dark grey bar). Values of pO2 were taken at the time points as indicated by numbers.
(C) Representative local field potential recordings in subfield CA3 during the time course of the experiment as shown in (A). Note that robust and persistent gamma oscillations (conditions 2 and 3) are completely blocked after 4-6 min of rotenone application (condition 6). For further details, see Kann et al., Brain, 2011.
Functional interactions between microglia and neurons
Microglia are tissue-resident macrophages in the CNS that become activated in most brain disorders, such as bacterial meningoencephalitis, multiple sclerosis, and Alzheimer’s disease. Activation of microglia features changes in morphology and receptor expression, antigen presentation, cytokine release, migration, and phagocytosis, and it ranges from proinflammatory and potentially neurotoxic to anti-inflammatory and neuroprotective phenotypes. The goal of this project is to identify the mechanisms that control the transition of microglia to various phenotypes in situ, including the impact on neuronal function and survival.
Papageorgiou IE, Lewen A, Galow LV, Cesetti T, Scheffel J, Regen T, Hanisch UK, Kann O.
TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ.
Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):212-7.
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.
Kann O, Huchzermeyer C, Kovács R, Wirtz S, Schuelke M.
Gamma oscillations in the hippocampus require high complex I gene expression and strong functional performance of mitochondria.
Brain. 2011 Feb;134(Pt 2):345-58.
Huchzermeyer C, Albus K, Gabriel HJ, Otáhal J, Taubenberger N, Heinemann U, Kovács R, Kann O.
Gamma oscillations and spontaneous network activity in the hippocampus are highly sensitive to decreases in pO2 and concomitant changes in mitochondrial redox state.
J Neurosci. 2008 Jan 30;28(5):1153-62.
Kann O, Kovács R, Njunting M, Behrens CJ, Otáhal J, Lehmann TN, Gabriel S, Heinemann U.
Metabolic dysfunction during neuronal activation in the ex vivo hippocampus from chronic epileptic rats and humans.
Brain. 2005 Oct;128(Pt 10):2396-407.