Zachary Freyberg, M.D., Ph.D.

  • Assistant Professor
  • Department of Psychiatry (Cell Biology-secondary)

Education & Training

  • B.S., Molecular Biophysics &Biochemistry-Yale University
  • M.S., Developmental &Molecular Biology-Albert Einstein College of Medicine
  • Ph.D., Developmental &Molecular Biology-Albert Einstein College of Medicine
  • M.D., Medicine-Albert Einstein College of Medicine

Research Interest Summary

Functional and structural characterization of dopamine signaling

Research Categories

Research Interests

Mechanisms of Dopamine Synaptic Vesicle Loading and Release:  We have developed a new experimental system using the Drosophila melanogaster genetic model to investigate the molecular mechanisms associated with presynaptic dopamine neurotransmission at the synaptic level. Taking advantage of the fly’s genetic tractability, we employ optical and genetic approaches using new fluorescent reporters of dopamine vesicle cargo and pH in 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 neuropsychiatric disease.

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 recent 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. Moreover, since D2-like dopamine receptors are the primary molecular targets of antipsychotic drugs, our work 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, we have 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 wildtype and islet-selective dopamine-receptor knockout mice.

In Situ Cryo-Electron Microscopy Approaches to Investigation of Secretion: To further examine vesicle physiology, we have 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 under near-native conditions for the first time. We are using these approaches to characterize the secretory system of pancreatic beta cells to reveal novel mechanisms of regulated secretion.

Representative Publications

Ballon JS, Pajvani U, Freyberg, Z, Liebel RL, Lieberman JA. Molecular pathophysiology of metabolic effects of antipsychotic medications. Trends Endocrinol Metab. 2014 Nov; 25(11): 593-600. PubMed PMID: 25190097.

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.

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.

Hiranita T, Freyberg Z. Importance of Substrate-Coupled Proton Antiport by the Vesicular Monoamine Transporter in the Actions of Amphetamines in Drosophila Brain. J Alcohol Drug Depend 2016 Dec 16; 4: e136. doi:10.4172/2329-6488.1000e136. PubMed PMID: 28164142.

McCarthy M, Freyberg Z. Dopamine D2 Receptors and the Circadian Clock Reciprocally Mediate Antipsychotic Drug Metabolic Disturbances. npj Schizophrenia 2017 Apr; 3(17): doi:10.1038/s41537-017-0018-4. PubMed PMID: 28560263.

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.

Freyberg Z, Aslanoglou D, Shah R, Ballon JS. Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia. Front. Neurosci. 2017; Jul. 11:432. doi: 10.3389/fnins.2017.00432. PubMed PMID: 28804444.

Pera M, Larrea D, Guardia-Laguarta C, Montesinos J, Velasco KR, Agrawal RR, Xu Y, Chan RB, Di Paolo G, Mehler MF, Perumal GS, Macaluso FP, Freyberg Z, Acin-Perez R, Enriquez JA, Schon EA, Area-Gomez, E. Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J. 2017 doi: 10.15252/embj.201796797. PubMed PMID: 29018038.

Carter SD, Mageswaran SK, Farino ZJ, Mamede JI, Oikonomou CM, Hope TJ, Freyberg Z, Jensen GJ. Distinguishing signal from autofluorescence in cryogenic correlated light and electron microscopy of mammalian cells. J Struct Biol. 2017. doi: 10.1016/j.jsb.2017.10.009. PubMed PMID: 29078993.

Full list of Publications