Zach Freyberg, MD, PhD

Dr. Freyberg’s research interests are based on his long-standing clinical interests in neuropsychiatric illnesses including schizophrenia and Parkinson’s disease and the contributions of the neurotransmitter dopamine to these disorders. His laboratory examines dopaminergic signal transduction in the central nervous system and periphery in vitro and in vivo utilizing a combination of genetics, pharmacology and both real-time live imaging and cryo-electron microscopy. Specifically, Dr. Freyberg’s lab focuses on three main projects:

1. Mechanisms of Dopamine Synaptic Vesicle Loading and Release:  Dr. Freyberg’s laboratory has developed a new experimental system using the fruit fly Drosophila melanogaster and mouse genetic models to investigate the molecular mechanisms associated with dopamine neurotransmission at the synaptic level. Taking advantage of the fly’s genetic tractability, the lab employs optical and genetic approaches using new fluorescent reporters of dopamine vesicle cargo and pH in the adult fly brain, which are concurrently validated in mammalian rodent models. This has led to new findings showing that dopaminergic vesicles use the neurotransmitter glutamate to modify their quantal size in response to depolarization. Ongoing work is further examining the physiological roles of dopamine/glutamate co-transmission in response to changes in dopamine neuron activity and the potential roles this may play in the development of a neuropsychiatric disease. Moreover, the Freyberg laboratory recently discovered evidence for glutamate’s role in modulating the vulnerability of dopamine neurons to neurodegeneration – a finding with implications in Parkinson’s disease.  
2. Dopamine’s Role in Regulation of Insulin Release and Antipsychotic Drug Action: The Freyberg laboratory’s recent work suggests that dopamine signaling outside the central nervous system also plays a key role in metabolism by mediating insulin release in pancreatic beta cells. Therefore, the lab is examining roles of dopamine and dopamine D2-like receptors in regulating a critical facet of pancreatic beta cell function – glucose-stimulated insulin secretion. Moreover, since D2-like dopamine receptors are the primary molecular targets of antipsychotic drugs, the lab also examines whether blockade of these peripherally-expressed receptors in beta cells plays an important role in the development of antipsychotic drug-induced metabolic disturbances. To examine these phenomena, the Freyberg laboratory has developed complementary experimental systems measuring dopamine receptors’ effects on both glucose-stimulated dopamine and insulin secretion in both an established pancreatic beta cell line as well as in pancreatic islets from wild-type and islet-selective dopamine-receptor knockout mice.
3. In Situ Cryo-Electron Microscopy Approaches to Investigation of Secretion: To further study dopamine vesicle physiology at the structural level, the Freyberg laboratory has begun applying cryo-electron microscopic (cryo-EM) approaches to study this process at super-resolution levels of detail. As a result, we have developed new imaging methods to visualize the distribution and trafficking of dopamine and insulin-containing vesicles in pancreatic beta cells and neurons under near-native conditions for the first time to reveal novel mechanisms of regulated neurotransmitter secretion. Dr. Freyberg is actively involved in the training and teaching in the Department of Psychiatry as well as through the Center for Neuroscience and the Integrative Systems Biology program with the aim of training new generations of physician-scientists and scientists interested in neurobiology and cell signaling and its applications to elucidating mental and neurological illnesses.