Killam Seminar Series: Think Positively

Kevin Beier

Associate Professor, Physiology & Biophysics School of Medicine, University of California, Irvine

Think Positively: Novel Mechanisms of Modulating Synaptic Plasticity and Implications for Brain Disease

Abstract: Administration of the Zeta Inhibitory Peptide (ZIP) interferes with memory maintenance and long-term potentiation (LTP). However, mice lacking its putative target, the protein kinase PKM2, exhibit normal learning and memory as well as LTP, making ZIP’s mechanism unclear. Here, we show that ZIP disrupts LTP by removing surface AMPA receptors through its cationic charge alone. This effect requires endophilin A2 (endoA2)-mediated endocytosis and is fully blocked by drugs suppressing macropinocytosis. ZIP and other cationic peptides selectively remove newly inserted AMPAR nanoclusters, providing a mechanism by which these peptides erase memories without altering basal synaptic function. When delivered in vivo, cationic peptides modulate memories on local and brain-wide scales and prevent memory loss in a model of traumatic brain injury. Our findings uncover a previously unknown synaptic mechanism by which memories are maintained or lost.

Bio: Kevin Beier obtained his bachelor’s degree in biochemistry, working in M. Thomas Record’s biophysics lab to explore the thermodynamic properties of protein-DNA binding. He earned his PhD in Dr. Connie Cepko’s genetics lab, where he developed viruses to map neuronal circuitry. He then completed his postdoc in Dr. Robert Malenka and Liqun Luo’s circuit neuroscience labs, investigating the neural circuit basis of behavior. Kevin developed the first monosynaptic anterograde viral tracer (Beier et al., PNAS 2011), created the Tracing the Relationship between Inputs and Outputs (TRIO) method to map the connectivity of the midbrain dopamine system (Beier et al., Cell 2015), and demonstrated that rabies virus transmission is cell activity-dependent, which allowed for the identification of key neural ensembles contributing to cocaine-induced behavioral changes (Beier et al., Nature 2017). His lab is focused on identifying vulnerability factors that contribute to a variety of neuropsychiatric disorders and developing methods to interrogate the basic mechanisms of normal and pathological learning.