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.
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.
| Gaviño, Michael A; Ford, Kevin J; Archila, Santiago et al. (2015) Homeostatic synaptic depression is achieved through a regulated decrease in presynaptic calcium channel abundance. Elife 4: |
