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Neuroscience Graduate Program at UCSF

Faculty - Steve Finkbeiner, M.D./Ph.D.

Molecular Mechanisms of Synaptic Plasticity and Neurodegeneration

Research Description

Our laboratory is interested in understanding the molecular mechanisms that underlie neuronal plasticity and those that lead to certain neurodegenerative diseases. Plasticity is the property of the nervous system that enables it to undergo long-lasting, sometimes permanent adaptive responses to brief stimuli, and it is important for establishing precise patterns of synaptic connections during early neuronal development and for learning and memory in older animals. Disturbances in plasticity and synaptic function could contribute significantly to memory disorders characteristic of some neurodegenerative diseases such as Huntingtonís, Parkinsonís, and Alzheimerís disease.

We are focusing on two problems related to plasticity. Work from several laboratories has suggested that brief stimuli lead to lasting adaptive responses in part through changes in new gene expression. We aim to elucidate the signal transduction pathways by which specific stimuli regulates synaptic function through gene transcription. We also aim to understand how new gene products get delivered to the specific synapses undergoing plasticity. During the course of this work, we have focused on particular genes, such as Arc, that are critical for memory consolidation. Recently, we have discovered a new kinase that is under the control of key glutamate receptors, which regulates AMPAR trafficking, neuronal gene transcription, synaptic plasticity and learning. We use multiple approaches to study mechanisms of neuronal plasticity and neurodegeneration. We use molecular biology and biochemistry techniques to identify and manipulate molecules that are involved in these processes and electrophysiology and imaging techniques to test the effects of these manipulations and to understand the roles of these molecules in synaptic structure and function. In selected cases, we make transgenic mice to study the effects of these pathways in vivo using behavior, physiology, imaging and histology.

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Current Projects

Please refer to:
Gladstone Insitute of Neurological Disease

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Lab Members

Michael Ando, Graduate Student
Rebecca Aron, Postdoctoral Fellow
Matthew Campioni, Postdoctoral Fellow
Lisa Elia, Research Associate
Kelly Haston, Postdoctoral Fellow
Ashkan Javaherian, Research Scientist
Julia Kaye, Postdoctoral Fellow
Amanda Mason, Graduate Student
Kelley Nelson, Administrative Assistant
Ana Osorio Oliveira, Graduate Student
Jeannette Osterloh, Postdoctoral Fellow
Gaia Skibinksi, Postdoctoral Fellow
Kurt Weiberth, Graduate Student
Hengameh Karagan Zahed, Graduate Student
Adam Ziemann, Reseach Fellow

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Selected Publications

    1. Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ. (1990) Glutamate induces calcium waves in cultured astrocytes: Long-range glial signaling. Science 247:470–473.
    2. Saudou F*, Finkbeiner S*, Devys D, Greenberg ME. (1998) Huntingtin acts in the nucleus to induce apoptosis, but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66. (*Authors contributed equally)
    3. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431:805–810. See also accompanying News and Views: Orr HT. Neuron protection agency. (2004) Nature 431:747–748.
    4. Rao VR, Pintchovski SA, Chin J, Peebles CL, Mitra S, Finkbeiner S. (2006) AMPA receptors regulate transcription of the plasticity-related immediate early gene Arc. Nat. Neurosci. 9:887–895.
    5. Pintchovski SA, Peebles CL, Kim HJ, Verdin E, Finkbeiner S. (2009) The serum response factor and a putative novel transcription factor regulate expression of the immediate-early gene Arc/Arg3.1 in neurons. J. Neurosci. 29:1525–1537.
    6. Finkbeiner S. (2010) Bridging the Valley of Death of therapeutics for neurodegeneration. Nat. Med. 16:1227–1232.
    7. Gittis AH, Hang GB, LaDow ES, Shoenfeld LR, Atallah BV, Finkbeiner S, Kreitzer AC. (2011) Rapid target-specific remodeling of fast-spiking inhibitory circuits after loss of dopamine. Neuron 71:858–868.
    8. Miller J*, Arrasate M*, Brooks E, Libeu CP, Legleiter J, Hatters D, Curtis J, Cheung K, Krishnan P, Mitra S, Widjaja K, Shaby BA, Lotz GP, Newhouse Y, Mitchell EJ, Osmand A, Gray M, Thulasiramin V, Saudou F, Segal M, Yang XW, Masliah E, Thompson LM, Muchowski PJ, Weisgraber KH, Finkbeiner S. (2011) Identifying polyglutamine protein species in situ that best predict neurodegeneration. Nat. Chem. Biol. 7:925–934. Featured in News and Views: Tonaka M. (2011) Nat. Chem. Biol. 7:861–862, & Research Highlights: Pastrana E. (2012) Nat. Methods 9:21.
    9. Sharma P, Ando DM, Daub A, Kaye JA, Finkbeiner S. (2012) High-throughput screening in primary neurons. Meth. Enzymol.506:331–360.
    10. HD iPS Consortium. (2012) Induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11:264–278.
    11. Serio A, Bilican B, Barmada SJ, Ando DM, Zhao C, Siller R, Burr K, Haghi G, Story D, Nishimura A, Carrasco M, Phatnani H, Shum C, Wilmut I, Maniatis T, Shaw CE, Finkbeiner S, Chandran S. (2013) Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc. Natl. Acad. Sci. U.S.A. 19:4697–4702.
    12. Korb E, Wilkinson CL, Delgado RN, Lovero KL, Finkbeiner S. (2013) Arc in the nucleus regulates synaptic PML-dependent GluA1 transcription and homeostatic plasticity. Nat. Neurosci. 16:874–883.
    13. Tsvetkov AS, Arrasate M, Barmada S, Ando DM, Sharma P, Finkbeiner S. (2013) Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat. Chem. Biol. 9:586–592

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