Graeme Davis

Department of Biochemistry and Biophysics
Programs in Neuroscience, Cell Biology and Developmental Biology
University of California, San Francisco
December 8, 2015

The Stable Brain: Homeostatic Control of Neural Function

A stable brain is a happy brain. Chemicals in the brain, the neurotransmitters, are charged with the Herculean task of maintaining homeostasis, or balance, in the functions of the brain. But how can the brain maintain homeostasis over a lifetime of changes? Dr. Davis and his lab examine the basic mechanisms that allow for homeostasis in brain circuits. In his talk, he discussed his work focusing on genetic mutations that may disrupt the processes of homeostasis, such as the release of chemical messengers that control the timing and firing of neurons.

The brain is astonishing in its complexity and capacity for change. This has fascinated scientists for more than a century. But, a paradigm shift is underway. It seems likely that the plasticity that drives our ability to learn and remember can only be meaningful in the context of otherwise stable, reproducible, and predictable baseline neural function. Without the existence of potent mechanisms that stabilize neural function, our capacity to learn and remember would be lost in the chaos of daily experience-dependent change. This underscores two great mysteries in neuroscience. How are the functional properties of individual neurons and neural circuits stably maintained throughout life? And, in the face of potent stabilizing mechanisms, how can neural circuitry be modified during neural development, learning and memory? We are seeking to answer to these questions by harnessing the powerful forward genetic tools of Drosophila and translating our findings into studies of the mammalian nervous system.

The mechanisms that stabilize neural function throughout life can be described as homeostatic. It has become clear that homeostatic signaling systems act throughout the central and peripheral nervous systems to stabilize the active properties of nerve and muscle. Evidence for this has accumulated by measuring how nerve and muscle respond to the persistent disruption of synaptic transmission, ion channel function, or neuronal firing. In systems ranging from Drosophila to human, cells have been shown to restore baseline function in the continued presence of these perturbations by rebalancing ion channel expression, modifying neuro transmitter receptor trafficking, and modulating neurotransmitter release. In each example, if baseline function is restored in the continued presence of a perturbation, then the underlying signaling systems are considered homeostatic.

A major goal of my laboratory is to define the cellular and molecular mechanisms that achieve the homeostatic control of presynaptic neurotransmitter release. This was the focus of my seminar. In brief, we are pursuing the first electrophysiology-based forward genetic screen for mutations that specifically disrupt the homeostatic modulation of synaptic transmission in vivo. I presented the most recent advances from our genetic studies. In doing so, I also discussed the bi-directional nature of the homeostatic signaling systems that control presynaptic neurotransmitter release, how bi-directional signaling is achieved at a cellular level, and new emerging molecular mechanisms.