The nervous system is constantly changing, yet is able to maintain stable structure and function. How is this accomplished? Homeostatic mechanisms in the nervous system have been described in a variety of organisms. In these systems, individual cells are able to maintain constant function despite perturbations affecting receptor input or ion-channel levels. Amazingly, such homeostatic regulation can occur over a period of only a few minutes. How this precise regulation of cellular function occurs in neurons, and the nature of the signaling mechanisms allowing for its rapid induction, are major questions only beginning to be explored. Importantly, homeostatic compensation has been observed following perturbations that either increase or decrease the levels of cellular parameters such as excitability or ion permeability. Studies to date, however, have focused solely on the mechanisms that allow for "homeostatic potentiation" in response to perturbations that reduce excitability. To achieve stability, "homeostatic depression" is equally important and must be equally robust. Because almost nothing is known mechanistically about homeostatic depression, I propose to 1) define the cellular features that are modulated to achieve homeostatic depression 2) to determine to what extent bi-directional homeostatic regulation (i.e. both homeostatic depression and potentiation) is carried out by a single underlying machinery and 3) to carry out a forward genetic screen to identify the first genes required for homeostatic depression. Because homeostasis in the nervous system is conserved from Drosophila to humans, understanding the sensing and signaling mechanisms that achieve neuronal stability should reveal novel and fundamental ways in which neurons self-regulate, a process important for preventing neurological dysfunction.

Public Health Relevance

Complex neurological diseases like schizophrenia, migraines and epilepsy affect countless people worldwide. It is widely speculated that many of these diseases may be due to the loss of stable function in neurons. The research I propose here will combine state of the art techniques with the simplicity of fruit fly genetics to investigate how neurons are able to achieve stability and how this process may underlie human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS086164-01
Application #
8646531
Study Section
Special Emphasis Panel (ZRG1-F03B-A (20))
Program Officer
Mamounas, Laura
Project Start
2013-12-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$47,114
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143