Spontaneous electrical activity plays central roles in nervous system development, helping to control how neurons migrate, make synaptic connections with one another, and develop their ability to generate electrical signals appropriate for their mature functions. How spontaneous activity is generated during nervous system development is only poorly understood. The present project results from the discovery in the last year of a striking form of spontaneous electrical activity in the mouse cerebral cortex near the time of birth. Brain slice calcium imaging methods revealed that on the day of birth (P0) neurons of the cortex generate spontaneous transient increases in intracellular calcium concentration ([Ca2+]i transients) that are highly synchronized across very large populations of nerve cells. These [Ca2+]i transients result from electrical activity, and occur synchronously in 60-80% of all cortical neurons in all cortical layers and regions. This activity is seen almost exclusively on the day of birth. The onset of this activity just before birth seems to be regulated by a large increase in Na+ current density, and the cessation of activity by a large increase in resting conductance just after P0. This project investigates the role of voltage-gated Ca2+ currents in admitting Ca2+ ions into the neurons during this spontaneous activity. Ca2+ is first step in the mechanism by which spontaneous activity carries out its developmental functions, and both the frequency of [Ca2+]i transients and the exact ion channels through which Ca2+ enters the cell are crucial parameters. The recent experiments have shown that there is a dramatic increase in total Ca2+ current density in cortical neurons near P0, suggesting that Ca2+ current development is coordinated with the activity. Patch clamp and Ca2+ imaging methods will be used to determine what Ca2+ channel subtypes are present in cortical neurons at P0, what the patterns of their development in the perinatal period are, and whether and to what extent they participate in Ca2+ entry leading to [Ca2+]i transients during spontaneous activity.
Intellectual merit. These experiments will elucidate how the intrinsic ion channel properties of cortical neurons, and the patterns of development of those channels, help shape developmentally critical spontaneous activity in the brain. The laboratory is one of the first to discover such activity in cortex, and to map the ion channel development leading up to it. The laboratory has also carried out extensive prior studies of ion channel development and the roles of spontaneous activity in invertebrate and amphibian preparations. The mechanism by which Ca2+ enters neurons during spontaneous activity is a primary determinant of how electrical activity carries out its important roles in nervous system development.
Broader impacts. In addition to adding fundamentally to our understanding of nervous system development, this project will occur in an environment particularly suited to integrating research and undergraduate education. As director of the undergraduate Neurobiology Major, Dr. Moody regularly advises undergraduate researchers in his own laboratory. In fact, the discovery of spnontaneous activity in mouse cortex was made by one such undergraduate, who presented her findings at the most recent Society for Neuroscience meeting. Experiments on Ca2+ current development in cortical neurons are being carried out by another undergraduate who has just started in the lab. In teaching the introductory course in the major, The Lab's research is brought into the classroom as an example of integrating biophysical and developmental studies of neurons.
