Malinow, Roberto - University of California, San Diego

研究领域

Dr. Malinow's research is directed towards an understanding of how the brain forms and stores memories. His laboratory examines how neuronal activity controls the strength of communication between neurons, at sites called synapses. Such synaptic plasticity is thought to underlie the formation and storage of memories. Synapses are key sites affected by diseases of cognition. It is believed that a detailed understanding of synaptic plasticity will identify critical steps that may be the targets of diseases such as Alzheimer's disease. Such an understanding may eventually lead to treatments that prevent the disease. Dr. Malinow uses a combination of techniques including patch clamp electrophysiology, two-photon laser scanning microscopy and molecular biology to examine the function and plasticity of synapses. He applies these techniques onto different animal models of normal function and disease. His research over the past decade has led him to focus on the biology of postsynaptic receptors. He has found that a change in the number of synaptic receptors, and long-term maintenance of this enhanced number of synaptic receptors, is a critical mechanism underlying synaptic plasticity. His studies further demonstrated that such a mechanism underlies a form of associative memory in rodents. More recently his laboratory has expanded into disease related studies, including Alzheimer's disease, schizophrenia and depression. In a series of studies he examined the effects of A-beta on synapses. A-beta peptide, a preteolytic product of APP, is thought to be central to the pathogenesis of Alzheimer's disease. However, the functional relationship of APP and A-beta to neuronal electrophysiology was not known. His laboratory has shown that neuronal activity modulates the formation and secretion of A-beta peptides from neurons. In turn, A-beta depresses synaptic transmission. Synaptic depression from excessive A-beta could contribute to cognitive decline during early Alzheimer's disease. In addition, activity-dependent modulation of A-beta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in Alzheimer's disease. These studies shed new light on the role of A? in normal and diseased states, and may lead to new treatments of Alzheimer's disease. His laboratory has recently begun to examine a synaptic basis for behavioral depression. They have found that in rat models of depression excitatory synapses are abnormally strong in a part of the brain that may act as a "disappointment center." Thus, negative rewards are likely heightened while positive rewards are diminished. They will use molecular, genetic, electrophysiological, optical and behavioral methods to test if these hyperactive synapses are responsible for behavioral depression.

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Park H, Rhee J, Park K, Han JS, Malinow R, Chung C. Exposure to stressors facilitates long-term synaptic potentiation in the lateral habenula. J Neurosci. 2017 May 24. Pii: 2281-16. Reinders NR, Pao Y, Renner MC, da Silva-Matos CM, Lodder TR, Malinow R, Kessels HW. Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3. Proc Natl Acad Sci U S A. Oct 18;113(42):E6526-E6534.(2016). Alfonso SI, Callender JA, Hooli B, Antal CE, Mullin K, Sherman MA, Lesné SE, Leitges M, Newton AC, Tanzi RE and Malinow R. Gain-of-function mutations in the kinase PKCα may promote synaptic defects in Alzheimer's Disease. Science Signaling May 10;9(427):ra47 (2016). Aow J, Dore K, Malinow R. Conformational signaling required for synaptic plasticity by the NMDA receptor complex. Proc Natl Acad Sci U S A. Nov 9. Nov 24;112(47):14711-6 (2015). Dore K, Aow J, Malinow R. Agonist binding to the NMDA receptor drives movement of its cytoplasmic domain without ion flow. Proc Natl Acad Sci U S A. Nov 24;112(47):14705-10 (2015). Shabel S, Proulx C, Piriz J and Malinow R. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment. Science 345:1494-8 (2014). Nabavi S, Fox R, Lin J, Tsien R, and Malinow R. Engineering memories with LTP and LTD. Nature 511(7509):348-52 (2014). Shabel SJ, Murphy RT and Malinow R. Negative learning bias is associated with risk aversion in a genetic animal model of depression. Frontiers in Human Neuroscience 8:1 (2014). Li K, Zhou T, Liao L, Yang Z, Wong C, Henn F, Malinow R, Yates JR 3rd, Hu H. βCaMKII in lateral habenula mediates core symptoms of depression. Science 341:1016-20 (2013). Nabavi S, Kessels H, Alfonso S, Aow J, Fox R, and Malinow R. Metabotropic NMDA receptor function is required for NMDA-dependent long-term depression. Proc. Nat. Ac. Sci 110:4027-32 (2013). Kessels H, Nabavi S and Malinow R. Metabotropic NMDA receptor function is required for Aβ-induced synaptic depression. Proc. Nat. Ac. Sci 110(10):4033-8 (2013). 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 131:160-173 (2007). Hsieh H., Boehm J., Sato C., Iwatsubo T., Tomita T., Sisodia S., and Malinow R. AMPA-R Removal Underlies A-beta-induced Synaptic Depression and Dendritic Spine Loss. Neuron 52:831-843 (2006). Rumpel, S., Ledoux, J., Zador, T. and Malinow R. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308:83-88 (2005). Takahashi, T., Svoboda, K. and Malinow, R. Experience strengthens transmission by driving AMPA receptors into synapses. Science 299:1585-1588 (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). Shi, S-H., Hayashi, Y., Esteban, J. and Malinow, R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105:331-343 (2001). Hayashi Y, Shi S, Esteban J, Piccini A, Poncer JC, and Malinow R: Driving AMPA receptors into synapses by CaMKII or LTP: Requirement of GluR1-PDZ-domain interaction. Science 287:2262-2267 (2000).