Zachary Z. Freyberg, MD, PhD

Assistant Professor, Psychiatry

Focus

Developing a better understanding of the molecular mechanisms by which synaptic vesicles dynamically load, retain and release neurotransmitters such as dopamine and how these processes contribute to neuropsychiatric illnesses

Research Summary

How do synaptic vesicles load and release their contents and how do these processes relate both to maintaining a healthy state or to neuropsychiatric diseases? The main goal of our laboratory has been to investigate these fundamental vesicular processes at cellular, molecular and whole animal levels, focusing on the dopamine system both in the central nervous system as well as peripherally in pancreas. We use a combination of novel genetic, pharmacological and imaging approaches in both mouse and Drosophila models to tackle these questions. The three ongoing areas of interest include: 1) examining the mechanisms of presynaptic dopamine vesicular neurotransmission primarily using the Drosophila melanogaster genetic model. We have been employing optical and genetic approaches using new fluorescent reporters of dopamine vesicle cargo and pH in adult fly brain to investigate how vesicles can modify their quantal size in a pH-dependent manner in response to depolarization or to psychostimulants including amphetamines.  2) Determining dopamine’s role in regulation of insulin release and antipsychotic drug action. Based on the recent discovery that pancreatic islets express the same dopamine signaling machinery as in brain, our work suggests that dopamine signaling outside the central nervous system also plays a key role in mediating insulin release. Therefore, we are examining roles of dopamine and dopamine D2-like receptors in regulating a critical facet of pancreatic beta cell function – glucose-stimulated insulin secretion in both wildtype mice and tissue-selective dopamine receptor knockout mice. 3) Use of new in situ cryo-electron microscopy approaches to investigate secretory vesicle trafficking. To further examine vesicle physiology, we have begun applying cryo-electron microscopic approaches to study this process at super-resolution levels of detail. The ultimate goal of our work is to develop novel treatments for disorders involving these fundamental processes including schizophrenia, addiction and Parkinson’s disease.

 

 

 

Summer Undergraduate Research Program

Yes

Publications

Freyberg Z, Sonders MS, Aguilar JI, Hiranita T, Karam CS, Flores J, Pizzo AB, Zhang Y, Farino ZJ, Chen A, Martin CA, Kopajtic TA, Fei H, Hu G, Lin YY, Mosharov EV, McCabe BD, Freyberg R, Wimalasena K, Hsin LW, Sames D, Krantz DE, Katz JL, Sulzer D, Javitch JA. Mechanisms of amphetamine action illuminated through in vivo optical monitoring of dopamine synaptic vesicles. Nature Communications 2016 Feb 16; 7:10652 doi: 10.1038/ncomms10652. PubMed PMID: 26879809.

Farino ZJ, Morgenstern TJ, Vallaghe J, Gregor N, Donthamsetti P, Harris PE, Pierre N, Freyberg R, Charrier-Savournin F, Javitch JA, Freyberg Z. Development of a homogenous time-resolved fluorescence assay for rapid insulin measurement. PLoS ONE 2016 Feb 5; 11(2): e0148684. PubMed PMID: 26849707.

Pizzo AB, Karam CS, Yano H, Freyberg RJ, Karam DS, Freyberg Z, Yamamoto A, McCabe BD, Javitch JA. The membrane-raft protein Flotillin-1 is essential for dopamine transporter-mediated amphetamine-induced behavior in Drosophila. Mol Psychiatry 2013 Jul; 18(7): 824-833. PubMed PMID: 22710269. 

Freyberg Z, Ferrando SJ, Javitch JA. Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action. Am J Psychiatry 2010 Apr; 167(4): 388-396.  PubMed PMID: 19917593.

Freyberg Z, Sweeney D, Siddhanta A, Bourgoin S, Frohman M, Shields D. Intracellular localization of phospholipase D1 in mammalian cells. Mol Biol Cell 2001 Apr; 12(4): 943-955. PubMed PMID: 11294898.