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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 stimul, 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 Huntington’s, Parkinson’s, and Alzheimer’s 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 such the influx of extracellular calcium or neurotrophin application regulates synaptic function through gene transcription. We also aim to understand how new gene products get delivered to the specific synapses undergoing plasticity. In a complementary approach, we are studying how a mutation in a single gene can lead to synaptic dysfunction and neurodegeneration in the neurological disorders, Huntington's and Parkinson’s disease. We have developed cellular models of each disease with the genes that encode the huntingtin and leucine-rich related kinase 2 proteins. These models have allowed us to manipulate the mutant genes to better understand the relationship between their structure and function. 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.

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Current Projects

Please refer to:
Gladstone Insitute of Neurological Disease

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Lab Members

Montserrat Arrasate
Research Scientist
Ph.D./Centro de Biologia Molecular, "Severo Ochoa", CSIC-Universidad Autonoma de Madrid, Spain

Hong Joo Kim
Postdoctoral Fellow
Ph.D./State University of New York at Stony Brook

Punita Sharma
Postdoctoral Fellow
Ph.D./Addenbrooke's NHS Trust, Open University, U.K.

Gaia Skibinski
Postdoctoral Fellow
Ph.D./University College of London, U.K.

Andrey Tsvetkov
Postdoctoral Fellow
Ph.D./University of Illinois Medical School

Maya Chandru
MD/PhD, and Biophysics Graduate Student
B.S./M.I.T.

Aaron Daub
MD/PhD, and Bioengineering Graduate Student
B.S/Stanford University

Erica Korb
Neuroscience and PIBS Graduate Student
B.S./Yale

Ian Kratter
MD/PhD, and BMS Graduate Student
B.A./UC Berkeley

Eva LaDow
Biopharmaceutical Sciences PSPG Graduate Student
A.B./Smith College

Jason Miller
MD/PhD, and CCB Graduate Student
B.S./Stanford University

Carol Peebles
MD/PhD, and Neuroscience Graduate Student
A.B./Princeton University

Hengameh Zahed
MD/PhD, and BMS Graduate Student
B.A./UC Berkeley

Lisa Elia
Research Associate
Ph.D./Albert Einstein College of Medicine

Tina Tran
Research Associate
B.S./UC Davis

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Selected Publications

    1. Finkbeiner SM, Stevens CF. (1988) Applications of quantitative measurements for assessing glutamate neurotoxicity. Proc. Natl. Acad. Sci. USA 85:4071–4074.

    2. Goldman RS, Finkbeiner SM. (1988) Therapeutic use of magnesium sulfate in selected cases of cerebral ischemia and seizure. N. Engl. J. Med. 319:1224–1225 [letter].

    3. Keanna JFW, McBurney RN, Scherz MW, Fischer JB, Hamilton PN, Smith SM, Server AC, Finkbeiner SM, Stevens CF, Jahr C, Weber E. (1989) Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties. Proc. Natl. Acad. Sci. USA 86:5631–5635.

    4. 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.

    5. Goldman RS, Finkbeiner SM, Smith SJ. (1991) Endothelin induces a sustained rise in intracellular calcium in hippocampal astrocytes. Neurosci. Lett. 11:4–8.

    6. Cornell-Bell AH, Finkbeiner SM. (1991) Ca2+ waves in astrocytes. Cell Calcium 12:185–204.

    7. Renzi R, Finkbeiner SM. (1991) Ciprofloxacin interaction with sodium warfarin. A potentially dangerous side effect. Am. J. Emerg. Med. 9:551–552.

    8. Finkbeiner SM. (1992) Calcium waves in astrocytes-filling in the gaps. Neuron 8:1101–1108. (This is a primary research paper, not a review).

    9. van den Pol TN, Finkbeiner SM, Cornell-Bell AH. (1992) Calcium excitability and oscillations in suprachiasmatic nucleus neurons and glia in vitro. J. Neurosci. 8:2648–2664.

    10. Finkbeiner SM. (1993) Glial calcium. Glia 9:83–104.

    11. Finkbeiner SM, Greenberg ME. (1996) Ca2+-dependent routes to Ras: Mechanisms for neuronal survival, differentiation, and plasticity? Neuron 16:233–236.

    12. Finkbeiner SM, Greenberg ME. (1997) Spatial features of calcium-regulated gene expression. Bioessay 19:657–660.

    13. Finkbeiner SM, Tavazoie SF, Maloratsky A, Jacobs K, Harris KM, Greenberg ME. (1997) CREB: A major mediator of neuronal neurotrophin responses. Neuron 19:1031–1047.

    14. Tao X, Finkbeiner SM, Arnold D, Shaywitz A, Greenberg ME. (1998) Ca2+-influx regulates BDNF transcription by a CREB family factor-dependent mechanism. Neuron 20:709–726.

    15. Finkbeiner SM, Dalva MB. (1998) To fear or not to fear: What was the question? A potential role for Ras-GRF in memory. Bioessays 20:691–695.

    16. Finkbeiner SM, Greenberg ME. (1998) Ca2+ channel-regulated neuronal gene expression. J. Neurobiol. 37:171–189.

    17. Saudou F*, Finkbeiner SM*, 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 to this work.)

    18. Curtis J, Finkbeiner SM. (1999) Sending signals from the synapse to the nucleus: Possible roles for CAMK, Ras/ERK, and SAPK pathways in the regulation of synaptic plasticity and neuronal growth. J. Neurosci. Res. 58:88–95.

    19. Finkbeiner SM. (2000) CREB couples neurotrophin signals to survival messages. Neuron 25:11–14.

    20. Finkbeiner SM. (2000) Calcium regulation of the brain-derived neurotrophic factor gene. Cell. Mol. Life Sci. 57:394–401.

    21. Finkbeiner SM. (2001) New roles for introns: Sites of combinatorial regulation of Ca2+- and cyclic AMP-dependent gene transcription. Sci. STKE 94:PE1–PE4.

    22. Bradley J, Finkbeiner S. (2002) An evaluation of specificity in activity-dependent gene expression in neurons. Prog. Neurobiol. 67:469–477.

    23. Humbert S, Bryson EA, Cordelières FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F. (2002) The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves huntingtin phosphorylation by Akt. Dev. Cell 2:831–837.

    24. Rao VR, Finkbeiner S. (2003) Secrets of a secretase: N-cadherin proteolysis regulates CBP function. Cell 114:533–535.

    25. Brooks L, Arrasate, M, Cheung K, Finkbeiner S. (2004) Using antibodies to analyze polyglutamine stretches. Methods Mol. Biol. 277:103–128.

    26. Arrasate M, Mitra S, Schweitzer E, Segal M, Finkbeiner S. (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431:805–810.

    27. Arrasate M, Finkbeiner S. (2005) Automated microscope system for determining factors that predict neuronal fate. Proc. Natl. Acad. Sci. USA.102:3840–3845.

    28. Peters-Libeu C, Newhouse Y, Krishnan P, Cheung K, Brooks E, Weisgraber K, Finkbeiner S. (2005) Crystallization and diffraction properties of the Fab fragment of 3B5H10, an antibody specific for disease-causing polyglutamine stretches Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. 61:1065–1068.

    29. Bradley J, Rao VR, Wang J, Carter S, Finkbeiner S. (2006) Splice variants of the NR1 subunit differentially induce NMDA receptor-dependent gene expression. J. Neurosci. 26:1065–1076.

    30. 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.

    31. Finkbeiner S, Cuervo AM, Morimoto RI, Muchowski PJ. (2006) Disease-modifying pathways in neurodegeneration. J. Neurosci. 26:10349–10357.

    32. Rao V, Carter S, Finkbeiner S. (2007) NMDA and AMPA receptors: Old channels, new tricks. Trends Neurosci. 30:284–291.

    33. Palop JJ, Chin J, Roberson ED, Wang J, Twin MT, Bien-Ly N, Yoo J, Ho KO, Yu G-Q, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. (2007) Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55:697–711.

    34. Mitra S, Finkbeiner S. (2008) The ubiquitination-proteasome pathway in Huntington’s disease. ScientificWorldJournal 8:421–433

    35. 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.

    36. Mitra S, Tsvetkov A, Finkbeiner S. (2009) Single neuron ubiquitin-proteasome dynamics accompanying inclusion body formation in Huntington's disease. J. Biol. Chem. 284:4398–4403.

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

Email

sfinkbeiner@gladstone.ucsf.edu

Phone

415-734-2508

Physical Address

1650 Owens Street
Room 308

Mailing Address

Gladstone Institute of Neurological Disease
1650 Owens Street, Office 308
San Francisco, CA 94158

For Internal Campus Mail

Box 1230

Other Websites

PIBS Website