Working Hypothesis & Aim
Based on experimental observations (Huchzermeyer et al., 2008 and preliminary works, unpublished), we believe that long-term neuronal signaling is accompanied by an incomplete restoration of ATP levels, successive depletion of adenine nucleotides and changes in ion distributions. As these alterations feed back to action potential firing and neurotransmitter release, regulatory mechanisms must exist ensuring robust network performance. By combining kinetic modeling with experiments in brain tissue we want to investigate neuronal exhaustion and its possible impact on network behavior.Experimental Fundament
The group of O. Kann has developed experimental settings to study mitochondrial functions and energy metabolism during various forms of neuronal activity in hippocampal slice preparations from healthy and pathologic brain (Jandova et al., 2006; Kann & Kovacs, 2007; Nateri et al., 2007).Theoretical Fundament
To address the question of neural exhaustion, we will apply kinetic modeling. As a pre-study, we established a simple kinetic model based on mass-action-kinetics (Iwamoto, Hoffmann & Holzhütter, unpublished). Here, it could be shown that depending on the length and the strenght of the stimulation irreversible ATP break down may lead to system crash.Work Program
Phase 1: Set-up of an electro-metabolic osmotic model (EMO) for a single neuron
Phase 2: Validation and refinement
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Phase 3: Simulation of network activities
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Researchers
Nikolaus Berndt
Johannes Eckstein
Prof. Hermann-Georg Holzhütter
Phase 1 of the project is being realized by Nikolaus Berndt. The other steps are part of the SFB 618 and are supervised by Prof. Hermann-Georg Holzhütter (computational partner) and Dr. Oliver Kann (experimental partner).
References
Huchzermeyer C, Albus K, Gabriel HJ, Otáhal J, Taubenberger N, Heinemann U, Kovács R, Kann O. (2008) 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., 28(5):1153-62. [PubMed]
Jandová K, Päsler D, Antonio LL, Raue C, Ji S, Njunting M, Kann O, Kovács R, Meencke HJ, Cavalheiro EA, Heinemann U, Gabriel S, Lehmann TN. (2006) Carbamazepine-resistance in the epileptic dentate gyrus of human hippocampal slices. Brain., 129(Pt 12):3290-306. [PubMed]
Kann O, Kovács R. (2007) Mitochondria and neuronal activity. Am J Physiol Cell Physiol., 292(2):C641-57. [PubMed]
Nateri AS, Raivich G, Gebhardt C, Da Costa C, Naumann H, Vreugdenhil M, Makwana M, Brandner S, Adams RH, Jefferys JG, Kann O, Behrens A. (2007) ERK activation causes epilepsy by stimulating NMDA receptor activity. EMBO J., 26(23):4891-901. [PubMed]