Ulli Bayer, PhD

Professor

 
Bayer_Ulli2

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

curriculum vitae​​

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.

3 translocation.png

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).