Ulli Bayer, PhD
Professor
Contact Information:
University of Colorado Denver
Department of Pharmacology
Mail Stop 8303, RC1-North
12800 East 19th Ave
Aurora CO 80045
Phone: (303) 724-3610
Fax: (303) 724-3663
E-mail: ulli.bayer@cuanschutz.edu
Office: RC1-North, P18-6106
Our field is molecular and cellular neuroscience. Specifically, we are interested in the molecular and cellular mechanisms underlying learning, memory and cognition. These higher brain functions are thought to require “synaptic plasticity”, i.e. changes in the strength of the synapses that form the connections between neurons. We are studying the mechanisms by which such changes at individual synapses are initiated and maintained. The main forms of plasticity that we are studying are long-term potentiation (LTP) and long-term depression (LTD) of excitatory synapses in the hippocampus, a brain region required for declarative learning and memory. We are also interested in how changes at one synapse are communicated to other nearby synapses. For instance, how do excitatory LTD-stimuli also cause long-term potentiation of inhibitory synapses (iLTP) on the dendrites of the same neuron?
Additionally, we apply our fundamental neuroscience findings to a better understanding of neurological disorders. This specifically includes conditions with aberrant synaptic plasticity, such as Alzheimer’s disease, Down syndrome, schizophrenia, and addiction. However, our recent advances also included neuroprotection after acute injuries such as stroke or global cerebral ischemia (Deng et al., 2017, Cell Rep; Buonarati et al., 2020, Cell Rep). We are particularly excited about the fact that studying the plasticity impairments in our disease-related projects also lead us to a better understanding of the fundamental mechanisms of how plasticity normally works.
Our techniques include sophisticated biochemistry; live-imaging of molecular interactions/movements in heterologous cells and neurons; whole-cell and field electrophysiology; and behavioral studies on mutant mice. The molecules in the focus of our interest are the NMDA-type glutamate receptor (NMDAR) and the Ca2+/calmodulin-dependent protein kinase II (CaMKII; for which we have published the 12meric holoenzyme structure; Myers et al. 2017, Nature Comm). The NMDAR is a Ca2+-conducting channel that is activated by glutamate, the major excitatory neurotransmitter in the mammalian brain; CaMKII is a robust sensor and frequency detector of the NMDAR Ca2+ influx and is unique as its activity can become Ca2+-independent (“autonomous”) after autophosphorylation at T286, a process regarded as molecular memory. The NMDAR and CaMKII have been recognized as central mediators of LTP for over 30 years, but our more recent findings demonstrated that CaMKII and its autonomous activity are also required for NMDAR-dependent LTD (Coultrap et al., 2014, Cell Rep). But how can CaMKII mediate both of these two opposing forms of synaptic plasticity? We are continuing to unravel the mechanisms that enable the intricate underlying signal computation by the CaMKII holoenzyme (Coultrap et al. 2014, Cell Rep; Goodell et al., 2017, Cell Rep; Cook et al., 2021 Science Adv). Intriguingly, CaMKII can also mediate the communication of plasticity at excitatory synapses to inhibitory synapses (Cook et al., 2021 Science Adv), further controlling the excitation/inhibition balance and adding another layer of cellular computation.
Regulation of synaptic strength by CaMKII involves the physical movement of the kinase to and from excitatory and inhibitory synapses. Stimulation-induced CaMKII translocation to excitatory synapses is largely dependent on a regulated direct binding of CaMKII to the NMDAR subunit GluN2B, a binding interaction we have intensively studies over the last 20 years (Bayer et al., 2001, Nature; Goodell et al., 2017, Cell Rep). We still want to address several important questions and apparent conundrums regarding the GluN2B interaction and translocation to excitatory synapses. For instance, how is input-specificity achieved? I.e. how is translocation to non-stimulated synapses prevented? Additionally, almost nothing is known to date about the mechanisms controlling translocation to inhibitory synapses. Excitingly, we now have a method that allows us to live-monitor the movement of endogenous CaMKII in neurons after different stimulation protocols (using intrabodies specific to CaMKII; published as cover article in Cook et al. 2019, Cell Rep). In contrast to over-expression of GFP-labelled CaMKII, expressing these intrabodies does not interfere with any type of stimulation-induced CaMKII movement that we have tested so far (by comparing the different live imaging methods to immunostaining).
Current Lab Members
 | Ulli BayerProfessor PhD Heinrich-Pette-Institute |
 | Olivia BuonaratiPostDoc BS Seattle University Fellowship: NIH F32 AG066536 |
Nicole BrownGraduate Student (Pharmacology) BS University of Colorado, Boulder | |
 | Sarah CookGraduate Student (Pharmacology) BS University of Texas at Austin |
 | Steve CoultrapSenior Research Associate BS University of Texas at San Antonio PhD Texas Tech University Health Science Center PostDoc University of Colorado |
 | Janna Mize-BergeProfessional Research Assistant BS University of Houston |
Nikki RumianGraduate Student (Neuroscience) | |
 | Jonathan TullisGraduate Student (Pharmacology) |
Previous Trainees
Hillary Allen, MS
Subsequent positions:
North-Face sponsored ultra trail runner
Kelsey Barcomb, PhD
Fellowship: NIH F31 NS083298
Subsequent positions:
PostDoc at Brown University, Providence, RI
Rebekah Borup, PhD
(formerly Rebekah Vest)
Fellowship: NIH F31 NS061584
Subsequent positions:
PostDoc at USC, Los Angeles, Dept. of Biology;
Adjunct Professor, Dept. of Biology, Mt San Antonio College, CA.
Isabelle Buard, PhD
Fellowship: Thorkildsen Fellowhip
Subsequent positions:
Research Instructor (faculty rank), UC Denver, Dept. of Neurology
Ron Freund, PhD
Subsequent positions:
Instructor (faculty rank), UC Denver, Dept. of Pharmacology
Dayton Goodell, PhD
Fellowship: NIH F31 NS092265
Subsequent positions:
PostDoc at University of Utah
Nicolas Haynes, BS
Subsequent positions:
graduate student, UC Boulder
Eric Horne, PhD
Subsequent positions:
PostDoc, U. Washington, Seattle, Dept. of Pharmacology;
Lead Scientist/Program Manager, Stella Therapeutics, Seattle;
Medical Science Liason, Lundbeck
Jacqueline Kulbe, BS
Subsequent positions:
MD/PhD student, University of Kentucky, Lexington
Heather O’Leary, PhD
Subsequent positions:
PostDoc, UC Denver, Dept. of Pediatrics
Vincent Zaegel, PhD
Subsequent positions:
Senior Professional Research Assistant, University of Colorado
Selected Review Article (of 9): (*: as corresponding author)
* Bayer, K. U. and Schulman, H. (2019) CaM kinase: Still inspiring at 40. Neuron, 103: 280-394
Free download here
Selected Research Articles(of >60): (*: as corresponding author, even if not listed last)
* Cook, S. G., Buonarati, O. R., Coultrap, S. J., and Bayer, K. U. (2021) CaMKII holoenzyme mechanisms that govern the LTP versus LTD decision. Science Advances. 7: eabe2300 https://advances.sciencemag.org/content/7/16/eabe2300
* Buonarati, O. R., Cook, S. G., Goodell, D. J., Chalmers, N. E., Rumian, N. L. Tullis., J. E., Restrepo, S, Coultrap, S. J., Quillinan, N., Herson, P. S., and Bayer, K. U. (2020) CaMKII versus DAPK1 binding to GluN2B in ischemic neuronal cell death after resuscitation from cardiac arrest. Cell Reports. 30: 1-8.
* Cook, S. G., Goodell, D. J., Restrepo, S., Arnold, D. B., and Bayer, K. U. (2019) Simultaneous live-imaging of three endogenous proteins reveals that β amyloid blocks the LTP-induced synaptic accumulation of CaMKII. Cell Reports. 27: 658-665. (cover article) https://doi.org/10.1016/j.celrep.2019.03.041
* Woolfrey, K., O’Leary, H., Goodell, D. J., Robertson, H., Horne, E., Coultrap, S. J., Dell’Acqua, M. L., and Bayer, K. U. (2018) CaMKII regulates the de-palmitoylation and synaptic removal of AKAP79/150 to mediate structural LTD. J. Biol. Chem. 293:1551-1567. (editor’s pick and cover article)
* Goodell, D. J., Zaegel, V., Coultrap, S. J., and Bayer, K. U. (2017) DAPK1 mediates LTD by making the CaMKII/GluN2B binding LTP-specific. Cell Reports 19:2231-2243.
* Myers, J., Zaegel, V., Coultrap, S. J., Miller, A., Bayer, K. U., and Reichow, S. L. (2017) The CaMKII holoenzyme structure in activation-competent conformations. Nature Commun. 8:15742. https://www.nature.com/articles/ncomms15742
* Deng, G., Orfila, J. E., Dietz, R. M., Moreno-Garcia, M., Coultrap, S. J., Quilinan, N., Traystman, R. J., Bayer, K. U., and Herson, P. S. (2017) Autonomous CaMKII activity as a drug target for histological and functional neuroprotection after resuscitation from cardiac arrest. Cell Reports 18:1109-1117.
* Barcomb, K., Hell, J. W. Benke, T. A., and Bayer, K. U. (2016) The CaMKII/GluN2B protein interaction maintains synaptic strength. J. Biol. Chem. 291:16082-16089.
* Coultrap, S. J., Freund, R., O’Leary, H., Sanderson, J., Roche, K., Dell’Acqua, M.L., and Bayer, K. U. (2014) Autonomous CaMKII mediates both LTP and LTD using a mechanism for differential substrate site selection. Cell Reports 6:431-437.
* Coultrap, S. J., and Bayer, K. U. (2014) Nitric oxide induces Ca2+-independent activity of the Ca2+/calmodulin-dependent protein kinase II (CaMKII). J. Biol. Chem. 289:19458-19465.
* Barcomb, K., Buard, I., Coultrap, S. J., Kulbe, J. R., O’Leary, H., Benke, T.A., and Bayer, K. U. (2014) Autonomous CaMKII requires further stimulation by Ca2+/calmodulin for enhancing synaptic strength. FASEB J. 28:3810-3819.
* Buard, I., Freund, R., Lee, Y.-S., Coultrap, S. J., Dell’Acqua, M. L., Silva, A. J., and Bayer, K. U. (2010) CaMKII "autonomy" is required for initiating but not for maintaining neuronal long-term information storage. J. Neurosci. 30:8214-8220.
* Vest, R. S., O’Leary, H., Coultrap, S. J., Kindy, M. and Bayer, K. U. (2010) Effective post-insult neuroprotection by a novel CaMKII inhibitor. J. Biol. Chem. 285:20675-20682.
* Bayer, K. U., LeBel, E., McDonald, G.L., O’Leary, H., Schulman, H. and DeKoninck, P. (2006) Transition from reversible to persistent binding of CaMKII to postsynaptic sites and NR2B. J. Neurosci.. 26:1164-1174.
* Bayer, K. U., De Koninck, P. and Schulman, H. (2002) Alternative splicing modulates the frequency-dependent response of CaMKII to Ca2+-oscillations. EMBO J., 21:3590-3597.
* Bayer, K.-U., De Koninck, P., Leonard, A.S., Hell, J.W. and Schulman, H. (2001) Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature, 411:801-805.
Bayer, K.-U., Harbers, K. and Schulman, H. (1998) aKAP is an anchoring protein for a novel CaM kinase II isoform in skeletal muscle. EMBO J., 17:5598-5605.
Positions:
We are currently seeking highly motivated individuals for postdoctoral positions. Those with experience in one or more of the following areas are especially encouraged to apply: electrophysiology, cell biology, live cell imaging, and super-resolution imaging. A number of projects incorporate a broad range of techniques, concepts and new tools, offering outstanding training potential. To apply for a postdoc position in the lab, please contact Dr. Bayer directly.
Graduate students should arrange rotations through their respective graduate programs. Dr. Bayer is currently a member of the University of Colorado MSTP, BSP, Pharmacology, Neuroscience, and Molecular Biology programs. Out of 20 previous three-months rotations, 9 resulted in authorships on publications from the lab, 2 of them as co-first authors (in J. Biol. Chem., Mol. Biol. Cell, PLoS One, and Brain Res.)
Current funding:
NIH R01 AG067713 (PI: Bayer; 25% effort) $2,447,725 08/01/2020 – 07/31/2025
“CaMKII nitrosylation in the age-related decline of synaptic plasticity” will investigate the mechanism and roles of CaMKII misregulation related to the cognitive decline during aging.
NIH R01 NS118786 (MPIs: Bayer/Herson; 12.5%) $1,943,750 01/15/2021 – 11/30/2025
“CaMKII in global cerebral ischemia: mechanisms and therapeutic intervention” will explore underlying disease mechanism and the possibility for extended therapeutic time windows.
NIH R01 NS110383 (Bayer/Dell’Acqua/Kennedy) $2,815,825 09/30/2018 – 06/30/2023
“Postsynaptic kinase/phosphatase networks in amyloid beta-induced synaptic dysfunction” will investigate the signaling mechanisms underlying synaptic pathology related to Alzheimer’s.
NIH R01 NS081248 (Bayer) $2,989,567 07/01/2013 – 03/31/2022
“CaMKII autophosphorylation in opposing directions of synaptic plasticity” will investigate the functions of newly discovered mechanisms of CaMKII substrate site selection in promotion of LTD versus LTP. This grant has been competitively renewed and is now in its 2nd funding period.
NIH F31 AG069458 (to Nicole Rumian) $ 71,156 03/05/21-02/28/23
“CaMKII hypo-nitrosylation in age-related decline of synaptic plasticity and cognition”
NIH F32 AG066536 (to Olivia Buonarati) $ 195,930 05/01/20-04/30/23
“APP signaling impairs CaMKII-dependent synaptic plasticity after ischemic brain injury”
NIH F31 AG062160 (to Sarah Cook) $ 69,594 05/01/2019-04/30/2021
“Suppression of CaMKII synaptic targeting and beta-amyloid pathology”