Kenneth G. Miller, Ph.D.
Genetic Models of Disease Research Program
Adjunct Professor, Oklahoma Center for Neuroscience
In terms of human health, my laboratory at the Oklahoma Medical Research Foundation contributes to understanding the genetic basis of human neurological diseases and disorders such as mental retardation syndromes, depression, memory disorders, schizophrenia, and sleep or anesthesia disorders.
My laboratory’s specific research mission is to understand how the brain transmits signals to control the flow of information between nerve cells or between nerve cells and muscle cells. The flow of information between nerve cells occurs at sites known as synapses. The human brain is literally packed with trillions of synapses. Like transistors in a computer, synapses perform complex computations and encode our memories; however, unlike transistors in a computer, synapses have the capacity to alter their state to allow learning. Information is transmitted from synapses in the form of a chemical known as a neurotransmitter. Synapses store packets of neurotransmitters in two types of tiny membranous sacs called synaptic vesicles and dense core vesicles. When a synapse receives the “right” signal, some of its synaptic vesicles fuse with the exterior membrane of the synapse and release a small bolus of neurotransmitter, thus transmitting a signal to an adjacent nerve cell.
Not all synapses are active. Some are ON (available for transmit information), while others are OFF (unavailable to transmit information). My research focuses on understanding the signals that nerve cells use to turn synapses ON or OFF, thus controlling the release of neurotransmitters. The brain’s ability to turn synapses ON and OFF is thought to form the basis for establishing, maintaining, and modifying behaviors and memories. In other words, the brain learns and remembers things by controlling which synapses are turned ON or OFF. Scientists currently have much to learn about how the brain and its nerve cells accomplish this amazing feat.
When investigating complex processes such as synaptic signaling, scientists often choose a simple “model organism”. Since synapses appear to function the same way in all animals, discoveries about how they work in simple model organisms are likely to be directly applicable to human biology and medicine. The round worm C. elegans has a “simple” nervous system with only 300 nerve cells and 5000 synapses. The C. elegans model allows me to use advanced genetic techniques to investigate synaptic signaling. Such techniques are currently not possible in humans or even mice.
One of the most powerful strategies for understanding “how things work” in biology is to intentionally mutate a model organism and identify mutants that disrupt whatever process you are studying. In my lab we use many different kinds of mutant screens, each of which involves examining thousands of individual animals to find to identify mutants defective in synaptic signaling. The simplest screens that we do simply involve looking for mutated worms that are either paralyzed (too little synaptic activity) or hyperactive (too much synaptic activity). Since mutations disrupt specific genes, identifying which genes are mutated in the synaptic signaling mutants allows us to identify the genes that are important for synaptic signaling. By identifying and analyzing hundreds of different synaptic signaling mutants, my research team and I have played a major role in discovering a complex molecular network that controls synaptic signaling within all synapses.
What are the human implications of this discovery? First, we know that all of the core components of the “Synaptic Signaling Network” are directly related to human genes. That means that understanding how worm synaptic signaling works is directly applicable to understanding the biology of the human brain. Second, our research has revealed that there are many gaps or “missing links” in our understanding of synaptic signaling. We are currently trying to identify these missing links by using various advanced genetic strategies. Discovering the missing links may provide important drug targets for human neurological diseases and disorders.
Note: The tiny roundworm C. elegans is one of the most intensively studied organisms on the planet. Researchers use it as a model for a understanding many different aspects of human biology and disease states, including cancer, cell death, development, aging, infection, neurological diseases, and basic cell biology. Since 2002, six C. elegansresearchers have shared three Nobel Prizes as a result of their pioneering studies using C. elegans.
B.S., Houghton College, Houghton, NY, 1985
Ph.D., Stanford University, Stanford, CA, 1993
Honors and Awards
1993-1996 Individual National Research Service Award (NIH)
Genetics Society of America
Society for Neuroscience
Joined OMRF Scientific Staff in 1993.
The broad goal of my lab is to understand how signaling within nerve cell synapses controls synaptic activity to produce behaviors. Since synapses are highly conserved in all animals, we have chosen to study them in the roundworm C. elegans where we can do large forward genetic experiments and other manipulations that are often impossible in other animals. The behavior we tend to focus on is locomotion, which is the most visually obvious output of the worm’s nervous system. Synapses control behaviors by using synaptic vesicles and dense core vesicles to release precise quantities of neurotransmitter onto a postsynaptic muscle cell or neuron. Voltage-gated calcium influx (triggered by a nerve impulse or action potential) is crucial for triggering release, but there is also a network of signal transduction pathways that tightly regulates synaptic activity by a poorly understood process. In C. elegans, and we think probably in all animals, this network can essentially turn synapses ON or OFF with respect to their ability to produce a behavior. C. elegans is ideally suited for investigating the layout and logic of this signaling network and how it functions in living animals during the execution of behaviors.
C. elegans researchers can identify the components of this Synaptic Signaling Network through forward genetic screens centered around easily recognizable phenotypes that affect locomotion, egg laying, and growth on a pesticide called aldicarb. Loss of function mutations in positive regulators tend to cause paralysis or strongly decreased rates of locomotion and egg laying as well as resistance to aldicarb, while loss of function mutations in negative regulators tend to cause hyperactive behaviors. Using large forward genetic screens, our lab and several others have uncovered the three major Gα pathways that control synaptic activity to produce the C. eleganslocomotion behavior. In this network, a core pathway controlled by the heterotrimeric G protein Gαq drives locomotion by a mechanism requiring both small synaptic vesicles and dense core vesicles. A second pathway, controlled by Gαo, inhibits the Gαq pathway to negatively regulate locomotion and synaptic activity. The third pathway, controlled by Gαs, produces the small signaling molecule cAMP and integrates with the Gαq and Gαo pathways to drive locomotion by a poorly understood mechanism.
One of the exciting things about this molecular circuit is that its components are all highly conserved in vertebrates, but the redundancy that often complicates analysis in vertebrates is largely lacking. However, there are predicted missing components in each pathway, and there are major gaps in our understanding of exactly how these pathways integrate to control synaptic activity and produce behaviors. These missing components and gaps are amenable to forward genetic investigation, which is a major focus of my lab. Over the past two years we have discovered a specific and interesting connection between a protein that regulates dense core vesicle release and the Gαs pathway, we have filled in a missing component of the Gαs pathway that is required for learning and memory in flies and has major clinical relevance to human disorders such as depression and schizophrenia, we have found the missing Gαq effector pathway and showed that, in the broad context of Gαq signaling in living animals, it is even more important than the canonical PLCβ pathway, and we have discovered the C. elegans light response and the novel light receptor and unusual neurons that mediate it. Much of our recent work focuses on the cell biology of dense core vesicles and the mysterious role they play in synaptic signaling.
In all but one of these discoveries, we used unbiased forward genetic screens to let the animal show us the important signaling pathways that animate its life. The pathways of the Synaptic Signaling Network are found in all animals, from worms to humans. Given their high level of conservation, these are probably the same basic pathways that help humans think, remember, learn, and sleep. Indeed, several components of this network, especially in the Gαs pathway, have been found to regulate learning and memory and sleep in various model systems and have been implicated in human neurological disorders such as schizophrenia and depression.
The forward genetic approaches that we use often reveal novel connections and molecules that would be missed by other strategies. For example, past forward genetic studies of this network have yielded novel synaptic signaling proteins that have counterparts in humans, such as UNC-13 (a synaptic vesicle priming protein), UNC-31 (a dense core vesicle priming protein), EGL-10 (a GAP for Gα proteins), RIC-8 (a GEF for Gα proteins), UNC-73 (the Gαq effector Trio RhoGEF), and UNC-108 (Rab2). Finding these novel connections enriches our understanding of the relationship between synaptic function and behavior and provides new potential drug targets for treating human neurological disorders.
Hoover CM, Edwards SL, Yu SC, Kittelmann M, Richmond JE, Eimer S, Yorks RM, Miller KG. A Novel CaM Kinase II Pathway Controls the Location of Neuropeptide Release from Caenorhabditis elegans Motor Neurons. Genetics 196:745-765, 2014. [Abstract] Featured article. See [Commentary] in same issue:196:601-604.
Edwards SL, Yu SC, Hoover CM, Phillips BC, Richmond JE, Miller KG. An Organelle Gatekeeper Function for Caenorhabditis elegans UNC-16 (JIP3) at the Axon Initial Segment. Genetics 194:143-161, 2013. [Abstract] Featured article. See [Commentary] in same issue.
Selected for [F1000Prime] and recommended as being of special significance in its field.
Edwards SL, Charlie NK, Richmond JE, Hegermann J, Eimer S, Miller KG. Impaired dense core vesicle maturation in Caenorhabditis elegans mutants lacking Rab2. J Cell Biol 186:881-895, 2009. [Abstract] Featured article. See In Focus in same issue: 186:769. [In Focus]
Edwards SL, Charlie NK, Milfort MC, Brown BS, Gravlin CN, Knecht JE, Miller KG. A novel molecular solution for ultraviolet light detection in Caenorhabditis elegans. PLoS Biol 6:e198, 2008. [Abstract] Featured article. See Synopsis in same issue: [Synopsis]
Williams SL, Lutz S, Charlie NK, Vettel C, Ailion M, Coco C, Tesmer JJ, Jorgensen EM, Wieland T, Miller KG. Trio’s Rho-specific GEF domain is the missing Gαq effector in C. elegans. Genes Dev 21:2731-2746, 2007. [Abstract]Featured article. See journal commissioned Perspective. [Perspective]
Charlie NK, Thomure AM Schade MA, Miller KG. The dunce cAMP phosphodiesterase PDE-4 negatively regulates Gαs – dependent and Gαs – independent cAMP pools in the Caenorhabditis elegans synaptic signaling network. Genetics 173:111-130, 2006. [Abstract]
Charlie NK, Schade MA, Thomure AM, Miller KG. Presynaptic UNC-31 (CAPS) is required to activate the Gαs pathway of the Caenorhabditis elegans synaptic signaling network. Genetics 172:943-961, 2006. [Abstract]
Reynolds NK, Schade MA, Miller KG. Convergent, RIC-8 – dependent Gα signaling pathways in the C. eleganssynaptic signaling network. Genetics 169:651-670, 2005. [Abstract]
Schade MA, Reynolds NK, Miller KG. Mutations that rescue the paralysis of C. elegans ric-8 (Synembryn) mutants activate the Gαs pathway and define a third major branch of the synaptic signaling network. Genetics 169:631-649, 2005. [Abstract]
Genetic Models of Disease Research Program, MS 48
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-1826
Fax: (405) 271-1827