Neurological diseases affect all age groups and segments of society in every country around the world. Many of these diseases are, at the most basic level, caused by the inability of circuits, synapses, and neurons to normally adjust to changes in their cellular environment resulting in an imbalance in neuronal activity. To treat these disorders, basic research is needed to understand how healthy neurons are able to sense, to compensate for, and to maintain a proper activity level. This proposal will add to the body of knowledge about how a healthy nervous system is able to remain plastic throughout a human lifetime while also maintaining functional connections in the face of change. Using Drosophila, where many of the basic neural molecules and proteins are conserved, provides a relatively simple, well-characterized system that has many powerful genetic tools to manipulate specific sub-groups of neurons. Using patch clamp electrophysiology, motor neurons in larval Drosophila can be directly recorded from to measure the neuron's firing properties and intrinsic properties. This work will investigate how motor neurons sense changes in their activity and set in motion a series of molecular steps beginning with calcium that results in changes to channels and conductances that affect cell excitability. Using a new technique, neurons will be activated by light during sensitive periods of development and the effect of this activity on the neurons wil be measured. In addition, the genetic tools available in Drosophila will be used to manipulate parts of the calcium pathway believed to be essential for a neuron to sense its own activity. This work will be the first in Drosophila to investigate how increased neuronal activity during specific periods of development can affect the excitability of individual neurons. It also directly addresses how individual neurons are able to sense and respond to changes in their local environment to maintain a preferred level of excitability over time by investigating a pathway that has been shown to be important in cellular excitability in a number of organisms including mammals. This work will lead to a better understanding of how many neurological diseases may develop and change over time, such as epilepsy.
This project will use genetic tools in Drosophila to study how individual neurons are able to sense, to compensate for, and to maintain preferred firing rates within a changing environment. This work promises to increase our understanding of the underlying cause of a large number diseases and disorders like epilepsy, where neurons with an inability to properly compensate in a changing environment can lead to pathological changes at synaptic, circuit, and behavioral levels.
