Jeremy Marks, M.D.

Developmental regulation of neuronal vulnerability to injury; polymer-mediated cell repair

Research Summary

A major focus of the laboratory is understanding the cellular and molecular mechanisms by which neuronal vulnerability to injury increases during postnatal maturation. We have developed techniques to maintain hippocampal neurons from postnatal animals in tissue culture. Using these cells, we investigate the intracellular mechanisms that underlie developmentally regulated neuronal responses to injury. Using time-lapse, multi-mode imaging of single neurons, we have found that vulnerability of cultured postnatal hippocampal neurons increases with postnatal age, and that this vulnerability increase depends on progressive loss of intracellular calcium ([Ca2+]_i) homeostasis. Because mitochondria play important roles in [Ca2+]i homeostasis, we have focussed on mitochondrial calcium ([Ca2+]mito) and membrane potential (Dy ) responses to excitotoxicity. We have found marked differences in excitotoxicity-induced Dy dissipation and Ca2+ accumulation as a function of postnatal age. These observations are consistent with the hypothesis that mitochondria are important determinants of the increased vulnerability to injury that accompanies maturation. Our observations that these differences depend on nitric oxide (NO) production have prompted our current studies of developmental differences in the magnitude of Ca2+-dependent NO synthesis, production of superoxide, and potential differences in cofactors for NO synthase. The central nature of mitochondrial function to the determination of neuronal vulnerability to injury has prompted us to begin determining developmental differences in mitochondrial mechanism of Ca2+ uptake and extrusion.

Selected Papers

Marks JD, Bindokas VP and Zhang XM. (2000) Maturation of vulnerability to excitotoxicity: intracellular mechanisms in cultured postnatal hippocampal neurons. Brain Res. Dev. Brain Res. 124 (1-2): 101-116, 11113517.

Nakamura K, Bindokas VP, Marks JD, Wright DA, Frim DM, Miller RJ and Kang UJ. (2000) The selective toxicity of 1-methyl-4-phenylpyridinium to dopaminergic neurons: the role of mitochondrial complex I and reactive oxygen species revisited. Mol. Pharmacol. 58 (2): 271-8, 0010908294.

Marks JD, Pan CY, Bushell T, Cromie C and Lee RC. (2001) Amphiphilic, tri-block copolymers provide potent, membrane-targeted neuroprotection (Summary). FASEB J. 15: 1107-1109.

Nakamura K, Bindokas VP, Kowlessur D, Elas M, Milstien S, Marks JD, Halpern HJ and Kang UJ. (2001) Tetrahydrobiopterin scavenges superoxide in dopaminergic neurons. J. Biochem. 276 (37): 34402-34407.

Waypa GB, Marks JD, Mack MM, Boriboun C, Mungai PT and Schumacker PT. (2002) Mitochondrial reactive oxygen species trigger calcium increases during hypoxia in pulmonary arterial myocytes. Circ. Res. 91 (8): 719-726.

Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G and Srisuparp P. (2003) Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N. Engl. J. Med. 349: 2099-2107.

Srisuparp P, Marks JD, Heitschmidt M, Khoshnood B and Schreiber MD. (2003) Predictive power of initial severity of pulmonary disease for subsequent development of bronchopulmonary dysplasia. Biol. Neonate 84: 31-36.

Kweon G-R, Marks JD, Krencik R, Leung EH, Schumacker PT, Hyland K and Kang UJ. (2004) Distinct mechanisms of neurodegeneration induced by chronic complex I inhibition in dopaminergic and non-dopaminergic cells. J. Biol. Chem. 279 (50): 51783–51792.

Kuznetsov A, Bindokas VP, Marks JD and Philipson LH. (2005) FRET-Based Voltage Probes For Confocal Imaging:  Membrane Potential Oscillations Throughout Pancreatic Islets. Am J Physiol Cell Physiol 289 (1): C224-229, 10.1152/ajpcell.00004.2005.

Li D, Marks JD, Schumacker PT, Young R M and Brorson JR. (2005) Physiological hypoxia promotes cortical neuron survival. Eur. J. Neurosci. 22: 1319-1326.

Marks JD, Boriboun C and Wang J. (2005) Mitochondrial nitric oxide mediates decreased vulnerability of hippocampal neurons from immature animals to NMDA. J. Neurosci. 25 (28): 6561-6575.

Mestan KL, Marks JD, Hecox K, Huo D and Schreiber MD. (2005) Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N. Engl. J. Med. 353 (1): 23-32.

Schreiber MD, Marks JD and Mestan KL. (2005) Response to correspondence re: Mestan KKL, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 2005;353:23-32. N. Engl. J. Med. 353 (15): 1626.

Seal JB, Buchh BN and Marks JD. (2006) New variability in cerebrovascular anatomy determines severity of hippocampal injury following forebrain ischemia in the Mongolian gerbil. Brain Res. 1073-1074C: 451-459.

Wang X, Deriy L, Foss SM, Huang P, Lamb FS, Kaetzel MA, Bindokas VP, Marks* JD and Nelson* DJ (*Co-senior Authors). (2006) ClC3 channels modulate excitatory synaptic transmission in hippocampal neurons. Neuron 52: 321-333, (highlighted in Nature 444:2, 2006).

Waypa GB, Guzy R, Mungai PT, Mack MM, Marks JD, Roe M and Schumacker PT. (2006) Increases in mitochondrial ROS trigger hypoxia-induced calcium responses in pulmonary artery smooth muscle cells. Circ. Res. 99: 970-978.