Zachary Z. Freyberg, MD, PhD

  • Assistant Professor, Psychiatry

Phone

(412) 648-0033

E-mail

freyberg@pitt.edu

Location

W1640 Biomedical Science Tower

Research Interest Summary

Molecular mechanisms of neurotransmitter release and their contribution to neuropsychiatric illness

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.

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. Authors share equal contribution.

 

Aguilar JI, Dunn M, Mingote S, Karam CS, Farino ZJ, Sonders MS, Choi SJ, Grygoruk A, Zhang Y, Cela C, Choi BJ, Flores J, Freyberg RJ, McCabe BD, Mosharov EV, Krantz DE, Javitch JA, Sulzer D, Sames D, Rayport S, Freyberg Z. Neuronal depolarization drives increased dopamine synaptic vesicle loading via VGLUT. Neuron 2017 Jul 17; 95(5): 1074-1088; 10.1016/j.neuron.2017.07.038. PubMed PMID: 28823729.

 

Steinkellner T, Zell V, Farino ZJ, Sonders MS, Villeneuve M, Freyberg RJ, Przedborski S, Lu W, Freyberg Z, Hnasko TS. Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons. J Clin Invest. 2018. Jan 16. pii: 95795. doi: 10.1172/JCI95795. PubMed PMID: 29337309.

 

Siegmund SE, Grassucci R, Carter SD, Barca E, Farino ZJ, Juanola-Falgarona M, Zhang P, Tanji K, Hirano M, Schon EA, Frank J, Freyberg Z. Three-dimensional analysis of mitochondrial crista ultrastructure in a Leigh Syndrome patient by in situ cryo-electron tomography. iScience 2018. Aug 1; 6C: 83-91; doi: 10.1016/ j.isci.2018.07.014. PubMed PMID: 30240627.

 

Farino ZJ, Morgenstern TJ, Maffei A, Quick M, De Solis A, Wiriyasermkul P, Freyberg RJ, Aslanoglou D, Sorisio D, Inbar B, Free R, Donthamsetti P, Mosharov E, Kellendonk C, Schwartz GJ, Sibley D, Schmauss C, Zeltser L, Moore H, Harris PE, Javitch JA, Freyberg Z. New roles for dopamine D2 and D3 receptors in pancreatic beta cell insulin secretion. Mol Psychiatry 2019. doi:10.1038/s41380-018-0344-6. PubMed PMID: 30626912.

 

Han F, Konkalmatt P, Mokashi C, Zhang Y, Ko A, Farino ZJ, Asico L, Xu G, Gildea G, Zheng X, Felder R, Lee REC, Jose P, Freyberg Z (co-corresponding author), Armando I. Dopamine D2 receptor modulates Wnt expression and control of cell proliferation. Scientific Reports 2019. 9, 16861 (2019) doi:10.1038/s41598-019-52528-4. PubMed PMID: 31727925.