McLean Hospital 115 Mill Street Belmont, MA 02478
Uwe Rudolph, Dr med, is interested in identifying functions of GABAA receptor subtypes in neuronal circuits, focusing on emotional regulation (anxiety, depression), drug abuse, autism, learning and memory, and the amnestic actions of general anesthetics. A second line of research is concerned with the development of etiological mouse models of schizophrenia, based on structural genomic variations found in patients. The goal of this research is to help elucidate the neurobiological basis of this disorder and to test novel strategies for therapeutic intervention.
Before joining McLean Hospital, Dr. Rudolph was an assistant professor of molecular neuropharmacology at the University of Zurich.
Dr. Rudolph’s Laboratory of Genetic Neuropharmacology, founded in 2005, investigates receptors for a brain chemical involved in several psychiatric conditions as a route to new treatments. In addition, they are developing new mouse models for studying schizophrenia.
Abnormalities involving the brain chemical GABA, a calming neurotransmitter, are related to depression, anxiety, schizophrenia, and other conditions. GABA is essential for balancing the activity levels in the brain. It binds to proteins called GABAA receptors—the targets for medicines used to treat anxiety disorders, insomnia, and seizures. GABAA receptors are the molecular substrates for the regulation of vigilance, anxiety, memory function, muscle tension, and epileptogenic activity. Identifying the functions of GABAA receptors forms the scientific basis for drug development.
Techniques used in Dr. Rudolph’s laboratory include behavioral analysis, molecular genetics, molecular biology, biochemistry, morphology, and optogenetics.
Dr. Rudolph and his lab investigate physiological and pharmacological functions of GABAA receptor subtypes in the central nervous system using mouse models in which a single mutated GABAA receptor subtype is no longer modulated by benzodiazepine drugs (knockin mice) or which are lacking a single GABAA receptor subtype in a defined group of nerve cells (conditional knock-out mice).
Using knockin point mutations in mice, Dr. Rudolph has demonstrated that anxiolytic and sedative actions of benzodiazepines, such as diazepam (Valium), are mediated by two distinct GABAA receptor subtypes and can thus be targeted separately pharmacologically.
The lab has generated “floxed” alleles of GABAA receptor subunit genes that allow us to ablate the respective subunit in a subregion specific manner—e.g., in hippocampal subregions or the amygdala—either via a cross with cre-transgenic mice or via stereotaxic injection of cre-expressing viruses into defined brain regions.
The animal models are analyzed using molecular biological, biochemical, morphological, and behavioral methods. The lab has also started to use optogenetic techniques which allows the group to modulate the activity of a specific subset of nerve cells in a reversible fashion. This will help clarify the cells’ functions during different stages of behavioral paradigms such as the acquisition, consolidation, retrieval and extinction of memory. Electrophysiological analysis is being performed by collaborating laboratories.
Dr. Rudolph focuses on the regulation of anxiety, mood, and reward, as well as cognition by subsets of GABAA receptors. The identification of functions of individual GABAA receptor subtypes is likely to enhance the understanding of fine-tuning of processes underlying central nervous system function. It could lead to novel therapeutic strategies for the treatment of anxiety, psychosis, memory, and mood disorders.
In a separate line of research, Dr. Rudolph and his staff are using chromosome engineering to generate mouse models with copy number variations (deletions and duplications) that are known risk factors for schizophrenia and autism in humans. These models enable the lab to study the neurobiological role of such structural genomic variants.
Current medicines for schizophrenia are unable to address cognitive deficits. Dr. Rudolph’s group is developing mouse lines that carry mutations found in patients with schizophrenia—specifically copy number variations, in which segments of DNA are either duplicated or deleted. Using these mutant mice, they study cognitive functions and develop interventions for improving cognitive deficits.
Engin E, Zarnowska ED, Benke D, Tsvetkov E, Sigal M, Keist R, Bolshakov VY, Pearce RA, Rudolph U. Tonic inhibitory control of dentate gyrus granule cells by α5-containing GABAA receptors reduces memory interference. Journal of Neuroscience 2015;35:13698-13712.
Behlke LM, Foster RA, Liu J, Benke D, Benham RS, Nathanson A, Yee BK, Zeilhofer HU, Engin E, Rudolph U. A pharmacogenetic “restriction-of-function” approach reveals evidence for anxiolytic-like actions mediated by α5-containing GABAA receptors in mice. Neuropsychopharmacology 2016;2492-2501.
Engin E, Smith KS, Gao Y, Nagy D, Foster RA, Tsvetkov E, Keist R, Crestani F, Fritschy JM, Bolshakov VY, Hajos M, Heldt SA, Rudolph U. Modulation of anxiety and fear via distinct intrahippocampal circuits. eLife 2016;5:e14120.
Belmont campus - Mailman Research Center, Room 123A