Grae Davis, PhD

Synapse Formation, Growth and Plasticity

The ultimate goal of my research program is to define, at a cellular and molecular level, how stable neural function is established and then maintained throughout the life of an organism. The research can be broken down into two main areas of investigation that are described below.

1. Homeostatic Regulation of Neural Function. The precise regulation of neural excitability is essential for proper nerve cell, neural circuit, and nervous system function. During postembryonic development and throughout life neurons are challenged with perturbations that can alter their excitability including changes in cell size, innervation, and synaptic function. An increasing number of experiments demonstrate that neurons are able to compensate for these types of perturbation and maintain appropriate levels of excitation. This type of compensation is defined as the homeostatic regulation of neural function. Increasingly, altered homeostatic regulation of neural function is hypothesized to participate in the cause and progression of neurological disease. However, the molecular mechanisms that achieve the homeostatic control of neural excitability remain largely unknown. We are taking advantage of the powerful genetic and functional genomic tools available in Drosophila to identify genes and signaling pathways that are involved in the homeostatic control of neural function. In particular, we are pursing the first electrophysiology-based forward genetic screen for mutations that specifically disrupt the homeostatic modulation of synaptic transmission in vivo. In doing so, we have recently identified mutations in genes that have been linked to neurological disease in human (Dickman and Davis, 2009). We are extending this research area to include collaborations with engineers and systems biologists with the goal of understanding how homeostatic signaling systems are designed and implemented within individual neurons and within complex neural circuitry.  It is widely hypothesized that these signaling systems will include molecular mechanisms that can sense and monitor neural activity over time as well as novel trans-synaptic signaling systems that can stabilize synaptic transmission and ion channel expression.  We anticipate that our molecular, genetic and electrophysiological studies of homeostatic signaling in the nervous system will inform our understanding of neural development, disease and aging.

2. Synapse Stabilization Versus Disassembly in Development and Disease. Throughout the nervous system there is evidence that the refinement and modulation of neural circuitry is driven not only by synapse formation, but also by the regulated disassembly of previously functional synaptic connections. Very little is known about the molecular mechanisms that regulate and execute synapse disassembly in the nervous system of any organism. We have developed high-throughput assays for synapse disassembly that allow us to screen the genome for the genes that, when knocked down or mutated, cause enhanced synapse disassembly and neural degeneration. Using this strategy we hope to define a core cellular program that controls synapse stability versus disassembly.  Recently, we have also initiated a new generation of genetic screen that is already identifying mutations that slow the progress of neuromuscular degeneration (Massaro et al., 2009; Keller et al., 2011). These mutations identify pro-degenerative signaling molecules that actively disrupt neural integrity. Our recent studies include identification of signaling systems that function between motoneurons and surrounding peripheral glia. We hypothesize that these genes and signaling systems will represent future targets for the development of small molecules capable of slowing the progression of neurodegenerative disease.

Lab Members

Lab Website

Academic community service and committee membership:
NS admissions committee, NS executive committee, Student-Faculty Diversity Committee TETRAD, Kavli Executive Committee, Boyer Executive Committee, Chancellor's Mission Bay Advisory Group, Kavli Executive Committee, Boyer Committee, Departmental Committee on Academic Promotions - Biochemistry and Biophysics. Workshops: grad student mental health. graduate student grant writing. Outreach: MBL Neurobiology Course (7 years), attended ABRCMS, Lecture and Support to Spines Course at the Marine Biological Laboratory (7 years). Other Program Memberships: Tetrad Graduate Program, SRTP student host, Experience: Mentored 17 graduate students through completion of PhD.