Scientific Achievements
Vollum Institute researchers have an unsurpassed reputation in unraveling the mysteries of synaptic regulation. Synapses are the tiny spaces between nerve cells that conduct the signals sent between cells. Their dysfunction underlies psychiatric diseases, and they have been a black box in neuropsychiatric research for decades. Drugs that are used to treat psychiatric disease and agents like tranquilizers, cocaine and amphetamines work by binding to these molecules.
Our scientists have illuminated synapses’ components, their atomic-level structures and how they mediate signals from one cell to another. Deepening our understanding how these central units of communication in the brain function will pinpoint precisely how psychotherapeutic drugs and other drugs work, enabling researchers to discover more effective ones.
Some of the pioneering researchers at the Vollum Institute
Eric Gouaux, Ph.D., a National Academy of Sciences member and Howard Hughes Medical Institute (HHMI) investigator, is recognized as one of the world-leading crystallographers in the area of neurotransmitter receptor and transporter structure. Dr. Gouaux recently published an x-ray structure of the NMDA receptor, found in nerve cells and critical for learning and memory, that gained worldwide attention. Last year, Dr. Gouaux published research filling a major gap in our understanding of addiction: how cocaine and amphetamines disrupt the normal functioning of the dopamine transporter in the brain. His discovery paves the way for developing treatments that could blunt the effects of cocaine and amphetamines in addicted patients. Dr. Gouaux's paper is the culmination of more than 20 years of work at the Vollum Institute investigating regulation of the critically important dopamine neurotransmitter system, proteins that have key contributions to such neuropsychiatric diseases as schizophrenia, depression, drug abuse behavior, and attention deficit disorder.
Gail Mandel, Ph.D., a member of the National Academy of Sciences and the American Academy of Arts and Sciences, has made major advances into understanding Rett syndrome, a congenital form of autism that primarily affects young girls. One such advance was showing in a mouse model that many symptoms of the disease could be alleviated by introducing a virus containing a normal copy of the gene responsible for the disease. Dr. Mandel and her lab are developing novel ways to overcome challenges to correcting disease-causing mutations in the nervous system without altering the physiological level of the corresponding messenger RNA. Their approach offers enormous potential for correcting genetic mutations, particularly those affecting the nervous system, and was selected for funding by an NIH Director's Transformative Research grant, the first such award at OHSU.
Kelly Monk, Ph.D., is an internationally recognized leader in the study of neuron-glia signaling and cell-cell interactions, in particular myelination. Myelin sheaths allow for rapid signal propagation along nerves, support long-term nerve health, and dynamically change to fine tune neuronal firing over long distances in the nervous system. How these sheaths form and undergo plastic changes had remained a mystery, despite the fact that changes in myelination underlie devastating neurological diseases like multiple sclerosis. Dr. Monk was instrumental in establishing zebrafish as a new model for the study of glial cells. Through forward genetics, she identified new mechanisms that govern glial cell biology and neuron-glial interactions, and she discovered that that the adhesion class G protein-coupled receptor (GPCR) GPR126 is essential for myelination in mammals. Dr. Monk’s work on GPR126 and other adhesion GPCRs has defined new functions for this class of receptors in the nervous system during development and neural repair. Her impressive molecular-genetic analyses have led to the understanding of how this enigmatic class of receptors are activated, the nature of their ligands, the delineation of downstream signaling mechanisms, and have identified GPR126 as a potential therapeutic target to promote neural repair. Dr. Monk continues to leverage the powerful genetic approaches in zebrafish with synergistic studies in mouse to uncover additional new mechanisms that govern neuron-glial interactions in the healthy and diseased nervous system.
Haining Zhong, Ph.D., introduced a new approach for analysis of synaptic mechanisms based on super-resolution microscopy. In recognition of his extraordinary promise, Dr. Zhong was selected for an NIH Director's Innovator Award, one of 20 such awardees in the country and the first from OHSU.
Vollum scientists were the first to discover…
- that the REST/coREST pathway determines whether a cell becomes a neuron, establishing that transcriptional repression serves as a gatekeeper of the neuronal phenotype
- the CREB binding protein, CBP, the first example of a transcriptional coactivator in metazoan organisms
- a microRNA pathway that amplifies the difference between neuronal and non-neuronal cells during development
- that reversal of a glial defect corrects symptoms of Rett syndrome, a neurodevelopmental disorder of young girls related to autism
- the concentration of the neurotransmitter, glutamate, within the synaptic cleft
- multivesicular release of neurotransmitters at individual synapses
- the magnesium block and calcium permeability of NMDA receptors, a core component of synaptic modulation
- crystal structures of glutamate receptors and transporters for glutamate and biogenic amines, uncovering new principles of receptor and transporter subunit organization and function. These studies revealed novel mechanisms of action of therapeutic agents, such as antidepressants
- the structure of the acid sensing ion channel, a component of pain-sensing pathways and possible target for drugs designed for treatment of stroke
- fundamental aspects of endo- and exocytosis, including the fusion pore as the transition state preceding full fusion of secretory vesicles. These studies lead to the first light microscopic imaging of single synaptic vesicles
- small conductance, calcium activated potassium (SK) channels in mammalian brain, leading to the characterization of calmodulin as the SK calcium sensor and the identification of a calcium-mediated negative feedback loop between SK channels and NMDA receptors in dendritic spines
- PACS1 as a cytosolic sorting protein required for trans-Golgi network localization. This pathway was later shown to be important for intracellular trafficking of proteins involved in HIV infection
- involvement of unconventional myosins and cadherin 23 in sensory mechanotransduction in hair cells of the inner ear