Nicholas C. Spitzer

Nicholas C. Spitzer

Professor of Biology, UCSD

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What are the mechanisms by which neurons differentiate to achieve the spectacular complexity of the brain? Remarkably, voltage-dependent ion channels and neurotransmitter receptors are expressed at early stages of development, substantially before synapse formation, suggesting that ion channel activity participates in signal transduction that directs subsequent steps of development. We have discovered that spontaneous transient elevations of intracellular calcium, generated by ion channels and receptors, control differentiation during an early period in embryonic development. Some of these calcium transients are terminated by subsequent development of voltage-dependent potassium current. Our work is aimed at understanding the mechanisms of generation of spontaneous calcium transients and the mechanisms by which they exert their effects, and at determining the molecular basis of regulation of potassium currents.



Calcium transients: mechanisms of generation and action. Two types of calcium transients, spikes and waves, drive transcriptional and posttranslational mechanisms in spinal neurons. They encode information in the frequency with which they are produced. A single type of calcium transient observed in myocytes resembles the waves observed in neurons. Since calcium spikes regulate appearance of the transmitter GABA in interneurons at the transcriptional level, we have analyzed their role in upregulation of transcripts encoding glutamic acid decarboxylase (GAD), the GABA synthetic enzyme. We are also investigating the mechanisms generating spontaneous calcium waves in neuronal growth cones in culture, and the roles of calcium transients in growth cone navigation in the intact spinal cord, using confocal microscopy to image intracellular calcium. Calcium transients regulate myofibrillogenesis in myocytes; our current aim is to elucidate the transduction cascade and determine if information is coded by frequency, as in neurons.



Potassium current: molecular mechanisms governing its expression. Generation of spontaneous calcium transients is restricted to an early period of development. Since calcium spikes are suppressed by the increase in voltage-dependent potassium current that eliminates long-duration calcium-dependent action potentials, we have investigated the molecular mechanisms by which this potassium current increases. We have examined the expression of genes of the Kv1-4 subfamilies using in situ hybridization in vivo and single cell RT-PCR in culture. We have recently cloned the Xenopus Kv3.1 and Kv4.3 genes, and are using antisense oligonucleotides to suppress expression of these genes and identify their functional contribution to the generation of current.







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Recent Publications



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Gu, X. and Spitzer, N.C. (1995) Distinct aspects of neuronal differentiation encoded by frequency of spontaneous Ca++ transients. Nature 375:784-787.

Rohrbough, J. and Spitzer, N.C. (1996) Regulation of [Cl-]i by Na+-dependent Cl- cotransport distinguishes depolarizing from hyperpolarizing GABAA receptor-mediated responses in spinal neurons. J. Neurosci.16:82-91.



Gurantz, D., Ribera, A.B. and Spitzer, N.C. (1996) Temporal regulation of Shaker- and Shab-like potassium channel gene expression in single embryonic spinal neurons during K+ current development. J. Neurosci. 16:3287-3295.



Schinder, A.F., Olson, E.C., Spitzer, N.C. and Montal, M. (1996) Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J. Neurosci. 16:6125-6133.



Ferrari, M.B., Rohrbough, J.C. and Spitzer, N.C. (1996) Spontaneous calcium transients regulate myofibrillogenesis in embryonic Xenopus myocytes. Dev. Biol. 178:484-497.



Gleason, E.L. and Spitzer, N.C. (1998) AMPA and NMDA receptors expressed by differentiating Xenopus spinal neurons. J. Neurophysiol. 79:2986-2998.



Ferrari, M.B., Ribbeck, K., Hagler, D.J. Jr. and Spitzer, N.C. (1998) A calcium signaling cascade essential for myosin thick filament assembly in Xenopus myocytes. J. Cell Biol. 141:1349-1356.



Jessen-Eller, K., Steele, M., Reinisch, C., and Spitzer, N.C. (1998) Blockade of ryanodine receptors stimulates neurite outgrowth in embryos of Spisula solidissima. Biol Bull. 195:206-207.



Olson, E.C., Schinder, A.F., Dantzker, J., Marcus, E.A., Spitzer, N.C. and Harris, W.A. (1998) Properties of ectopic neurons induced by Xenopus Neurogenin 1 misexpression. Molec. Cell. Neurosci. 12:281-299.



Gomez, T.M. and Spitzer, N.C. (1999) In vivo regulation of axon extension and pathfinding by growth cone calcium transients. Nature 397:350-355.



Rohrbough, J.C. and Spitzer, N.C. (1999) Changes in postsynaptic receptor colocalization and presynaptic transmitter release at developing excitatory spinal synapses. J. Neurosci. 19:8528-8541.



Ferrari, M.B. and Spitzer, N.C. (1999) Calcium signaling in the developing Xenopus myotome. Dev. Biol. 213:269-282.



Lautermilch, N.J. and Spitzer, N.C. (2000) Regulation of calcineurin by growth cone calcium waves controls neurite extension. J. Neurosci. 20:315-325.



Gurantz, D., Watt, S.D., Lautermilch, N.J. and Spitzer, N.C. (2000) Sustained upregulation of Xenopus Kv3.1 potassium channel gene transcripts in embryonic spinal neurons. J. Neurobiol. 42:347-356.



Vincent, A., Lautermilch, N.J. and Spitzer, N.C. (2000) Antisense suppression of a potassium channel gene demonstrates its role in maturation of the action potential. J. Neurosci. 20:6087-6094.



Watt, S.D., Gu, X., Smith, R.D. and Spitzer, N.C. (2000) Specific frequencies of spontaneous Ca2+ transients upregulate GAD 67 transcripts in embryonic neurons. Molec. Cell. Neurosci. 16:376-387.



Gomez, T.M., Robles, E., Poo, M.-m. and Spitzer, N.C. (2001) Filopodial calcium transients promote substrate-dependent growth cone turning. Science 291:1983-1987.



Ming, G., Wong, S.T., Henley, J., Yuan, X, Song, H., Spitzer, N. and Poo. M. (2002) Adaptation in the chemotactic guidance of nerve growth cones. Nature 417:411-418.



Gorbunova, Y.V. and Spitzer, N.C. (2002) Dynamic interactions of cAMP transients and spontaneous calcium spikes. Nature 418:93-96.







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Recent Reviews



Gu, X. and Spitzer, N.C. (1997) Breaking the code: regulation of neuronal differentiation by spontaneous calcium transients. Dev. Neurosci. 19:33-41.



Spitzer, N.C. and Gu, X. (1997) Purposeful patterns of spontaneous calcium transients in embryonic spinal neurons. Sem. Devel. Biol. 8:13-19.



Spitzer, N.C. and Sejnowski, T. J. (1997) Biological information processing: bits of progress. Science 277:1060-1061.



Jacquin, T.D., Yool, A., Benoit, E., Spitzer, N.C. and Moody, W.J. (1997) Petites cellules excitables deviendront grandes: le rythme pour la raison. Médecine/Science 14:63-71.



Spitzer, N.C. and Ribera, A.B. (1998) Development of electrical excitability in embryonic neurons: mechanisms and roles. J. Neurobiol. 37:190-197.



Spitzer, N.C. (1999) New dimensions of neuronal plasticity. Nature Neurosci. 2:489-491.



Spitzer, N.C., Lautermilch, N.J., Smith, R.D. and Gomez, T. M. (2000) Coding of neuronal differentiation by calcium transients. Bioessays 22:811-817.



Gomez, T. M. and Spitzer, N.C. (2000) Regulation of growth cone behavior by calcium: new dynamics to earlier perspectives. J. Neurobiol. 44:174-183.



Spitzer, N.C., Vincent, A. and Lautermilch, N.J. (2000) Differentiation of electrical excitability in motoneurons. Brain Res. Bull. 53:547-552.



Spitzer, N.C. (2002). Activity-dependent neuronal differentiation prior to synapse formation: the functions of Ca2+ transients. J. Physiol. 96: 73-80.



Spitzer, N.C., Kingston, P.A., Manning, T.J.Jr. and Conklin, M.W. (2002). Outside and in: development of neuronal excitability. Curr. Opin. Neurobiol. 12:315-323.