We use electrophysiological, optical, molecular and behavioral techniques to examine synapses and circuits underlying normal and abnormal brain function in rodents.
Several years ago we established AMPA receptor trafficking as a major component of synaptic potentiation in hippocampal slice LTP. By applying similar concepts and reagents we found that synaptic modification during fear conditioning was distributed among many neurons in the amygdala. Surprisingly, preventing plasticity in 10-20% of these neurons was sufficient to degrade significantly learning. These finding have implications regarding the nature of circuits that underlie memory.
In a project related to depressive disorders, we have found that a group of excitatory synapses in the lateral habenula are dramatically potentiated in rodent models of depression. The lateral habenula was recently shown to encode ‘disappointment’ signals in monkey studies. We seek to understand the nature of synaptic potentiation in this circuit and its relationship to mood disorders.
In a third project, we have found that beta amyloid, a key mediator in Alzheimer’s Disease, triggers LTD signaling pathways to remove synaptic AMPA receptors leading to eventual loss of synapses. We are interested in understanding the relation between circuit activity, beta amyloid formation and synaptic degradation.
Liao D Hessler N & Malinow R: Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice Nature 375:400-404 (1995).
Shi, S-H., Hayashi, Y., Esteban, J. and Malinow, R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105:331-43 (2001).
Zhu, J.J, Qin, Y., Zhao, M., Van Aelst, L., Malinow, R. Ras and Rap Control AMPA Receptor Trafficking during Synaptic Plasticity Cell 110:443-455 (2002).
Takahashi, T., Svoboda, K. and Malinow, R. Experience strengthens transmission by driving AMPA receptors into synapses. Science 299:1585-8 (2003).
Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S. and Malinow R. APP processing and synaptic function. Neuron 37:925-937 (2003).
Rumpel, S., Ledoux, J., Zador, T. and Malinow R. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308:83-8 (2005).
Hu, H, Real, E, Takamiya K, Kang M-G, LeDoux J, Huganir RL, and Malinow R. Emotion Enhances Memory via Norepinephrine Regulation of AMPA Receptor Trafficking. Cell 131:160-73 (2007).
Kessels HW, Kopec CD, Klein ME, Malinow R. Role of stargazin and phosphorylation in controlling subcellular distribution of AMPA receptors. Nature Neuroscience 12:888-96 (2009).
Makino H, Malinow R. AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron (in press).
Kessels HW, Malinow R. Synaptic AMPA receptor plasticity and behavior. Neuron. 61:340-50 (2009).