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.