Nicholas Spitzer

Nicholas Spitzer

Professor of Biology

 

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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, and 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 several aspects of differentiation during an early period in embryonic development. Our work is aimed at understanding the roles of electrical activity in assembly of the nervous system, by analyzing the effects of calcium transients on neuronal differentiation and determining the molecular mechanisms by which they exert these effects.

Specification of neurotransmitters and selection of transmitter receptors are processes that depend on patterned spontaneous embryonic calcium-dependent electrical activity. We are investigating the triggers of this spontaneous activity to understand its origins. We are studying activity-dependent regulation of expression of serotonin and dopamine in the embryonic brain, because these transmitters have broad impact on cognitive states and on behavior. We have begun analyzing the signaling mechanisms mediating activity-dependent transmitter specification, generating transgenic lines expressing fluorescent reporters of neurotransmitter synthesis to enable mutant screens. We are determining the extent to which there is environmental regulation of activity-dependent differentiation at early stages of development, revealing a partnership of electrical activity and genetic programs in the assembly of the nervous system.

Chang, L.W. and Spitzer, N.C. (2009) Spontaneous calcium spike activity in embryonic spinal neurons is regulated by developmental expression of the Na+, K+-ATPase b3 subunit. J. Neurosci. 29: 7877-7885.

Dulcis, D. and Spitzer, N.C. (2008) Illumination controls dopaminergic differentiation regulating behavior. Nature 456: 195-201.

Root, C.M., Velázquez-Ulloa, N.A., Monsalve, G.C., Minakova, E. and Spitzer, N.C. (2008) Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification. J. Neurosci. 28: 4777-4784.

Sann, S.B., Xu, L., Nishimune, H., Sanes, J.R. and Spitzer, N.C. (2008) Neurite outgrowth and in vivo sensory innervation mediated by a CaV2.2 - laminin b2 stop signal. J. Neurosci. 28: 2366-2374.

Borodinsky, L.N. and Spitzer, N.C. (2007). Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction. Proc. Natl. Acad. Sci. 104: 335-340.

Spitzer, N.C. (2006). Electrical activity in early neuronal development. Nature 444: 707-712.

Conklin, M.W., Lin, M.S. and Spitzer, N.C. (2005). Local calcium transients contribute to disappearance of pFAK, focal complex removal and deadhesion of neuronal growth cones and fibroblasts. Dev. Biol. 287: 201-212.

Spitzer, N.C., Borodinsky, L.N. and Root, C.M. (2005). Homeostatic activity-dependent paradigm for neurotransmitter specification. Cell Calcium 37: 417-423.

Spitzer, N.C., Root, C.M. and Borodinsky, L.N. (2004). Orchestrating neuronal differentiation: patterns of calcium spikes specify transmitter choice. Trends in Neurosci. 27: 415-421.

Borodinsky, L.N., Root, C.M., Cronin, J.A., Sann, S.B., Gu, X. and Spitzer, N.C. (2004). Activity-dependent homeostatic specification of transmitter expression in embryonic neurons. Nature 429: 523-530.

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

Ming, G., Scott T. 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.

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.

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 calcium transients upregulate GAD 67 transcripts in embryonic neurons. Molec. Cell. Neurosci 16: 376-387.

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.