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.
The frequency of transient elevations of intracellular calcium in growth cones regulates axon extension in identified neurons in situ. The image shows the preparation used to study this phenomenon - exposed nerve projections of an embryonic Xenopus spinal cord and notochord, double-labeled for β-tubulin (red) and actin (green) and visualized by confocal microscopy.
The image shows sibling tadpoles, one adapted to a dark background and the other to a white background. Natural light increases the number of dopaminergic neurons in the hypothalamus where camouflage behavior is controlled; dark exposure causes a decrease. Like endogenously dopaminergic neurons, neurons newly expressing dopamine drive this simple behavior. Such activity-dependent plasticity in the developing nervous system may be relevant to changes in cognitive states regulated by biogenic amines.
Nick Spitzer received his Ph.D. from Harvard University and was a postdoctoral fellow at Harvard and University College, London. He joined the faculty in 1972 and has been the recipient of a Sloan Fellowship, a Javits Neuroscience Investigator Award and a Guggenheim Fellowship. He is editor-in-chief of BrainFacts.org, a fellow of the American Association for the Advancement of Science, a member of the American Academy of Arts and Sciences and the National Academy of Sciences and director of the UCSD Kavli Institute for Brain and Mind.