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‘Inception of a false memory by optogenetic manipulation of a hippocampal memory engram’, Philosophical Transactions of the Royal Society B. Courtesy of X. Liu, S. Ramirez and S. Tonegawa
Scientific discussion meeting organised by Professor Tim Bliss FRS, Professor Graham Collingridge FRS and Professor Richard Morris FRS
This meeting brought together international experts in the field of synaptic plasticity to debate the underlying molecular mechanisms and discuss how these mechanisms are important for normal brain function, such as memory. This meeting also examined how pathological alterations in synaptic plasticity may underlie major brain disorders. Great progess has been made in each of these topics since a similar meeting was held at the Royal Society ten years ago, and it is now possible to see the outlines of a comprehensive neuroscientific account of how memory is encoded in the brain.
Biographies of the organisers and speakers are available below and you can also download the programme (PDF). Recorded audio of the presentations will be available on this page soon and the papers have been published in this issue of Philosophical Transactions B.
This meeting was immediately followed by a related satellite meeting at the Royal Society at Chicheley Hall, home of the Kavli Royal Society International Centre.
Enquiries: Contact the events team
Professor Tim Bliss FRS, MRC National Institute for Medical Research, UK
Tim Bliss was born in England and gained his PhD at McGill University in Canada. In 1967 he joined the MRC National Institute for Medical Research in Mill Hill, London, where he was Head of the Division of Neurophysiology from 1988 till 2006. His work with Terje Lømo in Per Andersen’s laboratory at the University of Oslo in the late 1960’s established the phenomenon of long-term potentiation (LTP) as the dominant synaptic model of how the mammalian brain stores memories. Since then he has worked on many aspects of LTP, including presynaptic mechanisms responsible for the persistent increase in synaptic efficacy that characterizes LTP, and the relationship between synaptic plasticity and memory. In May 2012 he gave the Croonian Lecture at the Royal Society on ‘The Mechanics of Memory’.
Professor Graham Collingridge FRS, University of Bristol, UKMultiple forms of NMDA receptor-mediated LTP at a hippocampal synapse
Long-term potentiation (LTP) comprises a family of mechanistically distinct forms of synaptic plasticity that varies according to the synapse under investigation and the developmental state of the preparation. Here we describe that, at the Schaffer collateral-commissural pathway of adult rats, there co-exists at least three forms of LTP (LTPa, LTPb and LTPc) that are induced by the synaptic activation of N-methyl-D-aspartate (NMDA) receptors. LTP(a) is a decaying phase of LTP (also known as STP). It is induced by the synaptic activation of GluN2B and GluN2D containing NMDARs and is expressed by an increase in the probability of neurotransmitter release (P(r)). LTP(b) is dependent on the synaptic activation of GluN2A and GluN2B containing NMDARs and does not involve a change in (P(r)). LTP(c) requires both PKA and protein synthesis. Its generation requires multiple spaced high frequency trains. A mechanism by which spaced theta burst stimuli (TBS) can induce LTP(c) will be presented.
Graham Collingridge is the Professor of Neuroscience in Anatomy in the School of Physiology & Pharmacology at the University of Bristol, UK. From 1999 until 2012 he was also the Director of the MRC Centre for Synaptic Plasticity. In 2001 he was elected a fellow of The Royal Society. His research interests are in the molecular mechanisms of synaptic plasticity. He is particularly interested in how glutamate receptors and their downstream effectors are involved in the mechanisms of long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus and other regions of the mammalian brain.
Professor Richard Morris CBE FRS, University of Edinburgh, UK
Richard Morris is Professor of Neuroscience at the University of Edinburgh and Director of the Centre for Cognitive and Neural Systems. He read Natural Sciences at the University of Cambridge followed by a D.Phil at Sussex University. He moved to Scotland in 1977 where he developed the watermaze in the Gatty Marine Laboratory at the University of St Andrews, moving in 1986 to the University of Edinburgh where he was appointed full Professor in 1993. His scientific interests are in the neurobiology of learning and memory, and his research included the first demonstration that hippocampal NMDA receptors are necessary for spatial learning, the development of the synaptic tagging and capture hypothesis of protein synthesis-dependent long-term potentiation and, most recently, work on the role of mental schemas in systems consolidation. He is an elected Fellow of the AAAS, of the American Academy of Arts and Sciences, and of the Norwegian Academy of Science and Letters, and was elected a Fellow of the Royal Society in 1997. He was appointed a CBE in 2007.
Professor Mark Bear, Howard Hughes Medical Institute and MIT, USALong-term depression: From amblyopia to autism
It has been 50 years since Wiesel and Hubel (1963) first reported that cortical neurons in V1 rapidly lose responsiveness to an eye that is temporarily deprived of patterned vision. Based on a theoretical analysis of ocular dominance plasticity, it was hypothesized that loss of visual cortical responsiveness after monocular deprivation (MD) is a consequence of excitatory synaptic weakening that is driven by poorly correlated “noise” originating in the deprived retina. We subsequently established that weak afferent stimulation indeed triggers homosynaptic long-term depression (LTD) in hippocampus and V1, and showed that the mechanisms of LTD are necessary and sufficient to account for the loss of visual responsiveness after MD. Studies in the hippocampus additionally revealed that one form of LTD is triggered by activation of metabotropic glutamate receptor 5 (mGluR5) and requires immediate translation of mRNA in dendrites. These findings begged the questions of how mGluR5 initiates protein synthesis in dendrites, how the requisite mRNA translation is regulated, and how newly synthesized proteins stabilize LTD. In the course of addressing these questions, we discovered that mGluR-LTD is exaggerated in the Fmr1-/y (KO) mouse model of human fragile X syndrome, a heritable cause of autism and intellectual disability. This modest finding provided the insight that eventually culminated in the “mGluR theory” of fragile X which proposes that exaggerated protein synthesis downstream of mGluR5 is pathogenic and contributes to multiple symptoms of the disease. Research performed by many labs over the past decade has validated this concept, and firmly established that diverse fragile X phenotypes in several animal models can indeed be corrected by partial inhibition of mGluR5 signaling. Clinical trials based on these findings have been launched in both fragile X and idiopathic autism. The realization that small molecule therapies can modify developmental brain disorders once considered intractable has ushered in a sea change in how these disorders are viewed medically. In no small part, the origins of this advance can be traced to the fundamental investigation of synaptic plasticity.
Dr Mark Bear is an Investigator of the Howard Hughes Medical Institute, and Picower Professor of Neuroscience in The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology. Dr Bear served as Director of The Picower Institute from 2007 to 2009. Prior to moving to MIT in 2003, Dr Bear was on the faculty of Brown University School of Medicine for 17 years. After receiving his B.S. degree from Duke University, he earned his Ph.D. degree in neurobiology at Brown. He took postdoctoral training from Wolf Singer at the Max Planck Institute for Brain Research in Frankfurt, Germany, and from Leon Cooper at Brown. Bear’s laboratory has substantially advanced knowledge of how cerebral cortex is modified by experience. He made fundamental discoveries on bidirectional synaptic plasticity, metaplasticity, the molecular basis of amblyopia (a cause of visual disability in children), and the pathophysiology of fragile X syndrome (the most common inherited cause of intellectual disability and autism). He has been at the forefront of the efforts to translate knowledge of autism pathophysiology into new treatments.
Professor Mu-ming Poo, University of California, Berkeley and Institute of Neuroscience, Chinese Academy of SciencesSpike timing-dependent plasticity and BDNF secretion
In acute hippocampal slices, the presence of extracellular brain-derived neurotrophic factor (BDNF) is essential for the induction of spike timing-dependent long-term potentiation (tLTP). In a reduced system of dissociated hippocampal neurons in culture, repetitive pairing of glutamate pulses at the dendrite with neuronal spikes could induce persistent alterations of glutamate-induced responses at the same dendritic site in a manner that mimics spike timing-dependent plasticity (STDP). By monitoring changes in the GFP fluorescence at the dendrite of hippocampal neurons expressing GFP-tagged BDNF, we found that pairing of iontophoretic glutamate pulses with neuronal spiking resulted in BDNF secretion from the dendrite at the iontophoretic site only when the glutamate pulses were applied within a time window of ~40 ms prior to neuronal spiking, indicating BDNF secretion could be triggered in spike timing-dependent manner from the postsynaptic dendrite. In corticostriatal synapses, BDNF is also required for TBS-induced LTP. However, striatal BDNF was found to be stored in cortical axons rather than postsynaptic striatal cells. Here we found presynaptic BDNF secretion depends on activation of axonal NMDA receptors. Genetic deletion of BDNF or the GluN1 subunit of NMDA receptors selectively in cortical axons abolished LTP. Taken together, these results showed that BDNF is essential for activity-induced LTP and either pre- and postsynaptic secretion of BDNF could support LTP induction.
Mu-ming Poo received B.S. degree in physics in 1970 from the Tsinghua University (Taiwan) and his PhD in biophysics from Johns Hopkins University in 1974. He had served on the faculty of University of California at Irvine, Yale University, Columbia University, and University of California at San Diego, before joining University of California, Berkeley in 2000, where he is currently Paul Licht Distinguished Professor in Biology. Since 1999, he also served as the founding Director of Institute of Neuroscience, Chinese Academy of Sciences in Shanghai. Poo had received Ameritec Prize (2001), Docteur Honoris Causa from Ecole Normale Supérieure, Paris (2003), P. R. China International Science & Technology Cooperation Award (2005), and Qiushi Distinguished Scientist Award (2011). He is a member of Academia Sinica, US National Academy of Sciences, and Chinese Academy of Sciences. His research interests include neuronal differentiation, axon guidance, and synaptic plasticity.
Professor Dimitri Kullmann, University College London, UKLTP at glutamatergic synapses on hippocampal interneurons
Until recently LTP has been widely assumed to be an exclusive property of glutamatergic synapses on principal cells. Recent advances in classifying interneurons into different subtypes has however helped to reveal several patterns of use-dependent plasticity. Some interneurons exhibit NMDA receptor-dependent LTP, despite absence of calcium/calmodulin-dependent kinase II. Other interneurons exhibit NMDA receptor-independent LTP, which depends instead on calcium-permeable AMPA and group I metabotropic glutamate for induction. Several lines of evidence point to a presynaptic locus of expression for NMDA receptor-independent LTP, although the putative retrograde messenger remains elusive. Remarkably, both types of LTP exhibits pathway specificity, implying compartmentalisation of signalling cascades in interneurons despite absence of profuse dendritic spines. Among the computational roles proposed for LTP in interneurons are regulation of circuit excitability and preservation of temporal fidelity of local circuit computations in the face of LTP in principal cells.
Dimitri Kullmann studied Medicine and Physiology at Oxford and London. Following postdoctoral research in San Francisco with Roger Nicoll he established his own laboratory at the Institute of Neurology where he continues to direct a research group. His research interests include mechanisms of synaptic plasticity, neurological channelopathies, experimental epilepsy and computational properties of simple neural circuits. He also works as a neurologist at the National Hospital, Queen Square.
Professor Gina Turrigiano, Brandeis University, USAHomeostatic plasticity
It has been postulated that homeostatic mechanisms maintain stable circuit function by keeping neuronal firing within a set point range, but whether neurons in vivo exhibit such firing rate homeostasis has not been directly demonstrated. I will discuss recent experiments in which we used chronic multielectrode recordings to monitor firing rates in visual cortex of freely behaving rats during chronic monocular visual deprivation (MD). Firing rates in V1 were suppressed over the first 2 day of MD but then rebounded to baseline over the next 2–3 days despite continued MD. This drop and rebound in firing was accompanied by bidirectional changes in mEPSC amplitude measured ex vivo. The rebound in firing was independent of sleepwake state but was cell type specific, as putative FS and regular spiking neurons responded to MD with different time courses. These data establish that homeostatic mechanisms within the intact CNS act to stabilize neuronal firing rates in the face of sustained sensory perturbations.
Gina Turrigiano received her BA from Reed College and her PhD from UC San Diego. She then trained as a postdoc with Eve Marder at Brandeis University before joining the faculty in 1994, where she is now a full professor. Her scientific interests include mechanisms of synaptic and intrinsic plasticity and the experience-dependent refinement of neocortical microcircuitry. She has received numerous awards for her research including a MacArthur foundation fellowship, a McKnight Technological Innovations Award, an NIH director’s pioneer award, and the HFSP Nakasone award. She is a member of the American Academy of Arts and Sciences and the National Academy of Sciences.
Professor Roger Nicoll, University of California, San Francisco, USAExpression mechanisms underlying long-term potentiation: a postsynaptic view – ten years on
I will focus on the mechanisms underlying the postsynaptic expression of LTP. More specifically I will discuss recent work on the trafficking of AMPARs. These experiments involve a molecular replacement strategy, in which the endogenous AMPARs are genetically deleted and replaced with mutated receptors. The results suggest that recruitment of receptors during LTP is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors. The most parsimonious explanation for these results is that during LTP, slots, which do not distinguish among glutamate receptor subunit types, are added to the PSD. This recruitment is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors.
Roger Nicoll received his medical training at the University of Rochester School of Medicine and his research training at the National Institutes of Health. Following work with Nobel laureate John Eccles he joined the University of California at San Francisco where he has remained. He has used in vitro brain slice preparations to define the numerous neurotransmitters that mediated synaptic transmission and characterized how these neurotransmitters control neuronal excitability and plasticity. More recently he has discovered a family of auxiliary receptor proteins that are essential for the activity dependent trafficking of synaptic glutamate receptors, a process thought to underlie certain forms of learning and memory. For his contributions he has received numerous awards including election to the National Academy of Science.
Professor Alan Fine, Dalhousie University, CanadaLTP Expression: Reconciling the Preists and the Postivists
Long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus has been intensively investigated over the past four decades. Where and how LTP is actually expressed, however, remain controversial issues. Much evidence has been offered supporting both pre- and post-synaptic contributions to LTP expression. Although it is widely held that postsynaptic expression mechanisms are the primary contributors to LTP expression, evidence for that conclusion is amenable to alternative explanations, and our own data support a dominant presynaptic role. Recognition of the state-dependency of expression mechanisms, and consideration of the consequences of the spatial relationship between postsynaptic glutamate receptors and presynaptic vesicular release sites, lead to a model that may reconcile views from both sides of the synapse.
Alan Fine is University Research Professor at Dalhousie University in Halifax, Nova Scotia. He was formerly a team leader at the National Institute for Medical Research in Mill Hill. He received his undergraduate education at Harvard University and graduate degrees from the University of Pennsylvania, and did postdoctoral research at the National Institute for Mental Health in Washington, DC, the Weizmann Institute of Science in Rehovot, and the University of Cambridge and MRC Centre in Cambridge before moving to Nova Scotia, where he lives with his wife and three children. In addition to his research on synaptic function and plasticity, his other research interests have included the development of optical tools for studying neural function, and neural reconstruction by cell transplantation; he is currently developing lensless microscopy for a wide range of applications.
Dr Erin Schuman, Max-Planck Institute for Brain Research, GermanyMaintaining and modifying the synaptic proteome
An individual neuron in the brain possesses approximately 10,000 synapses, many of which are hundreds of microns away from the cell body, which can process independent streams of information. During synaptic transmission and plasticity, remodeling of the local proteome occurs via the regulated synthesis of new proteins. I will discuss previous and current studies aimed at understanding how protein synthesis is regulated in neurons.
Erin Schuman was born in 1963 in California. After completing her BA in Psychology at the University of Southern California in 1985, Erin Schuman received her PhD. in Neuroscience from Princeton University in 1990. She conducted postdoctoral studies in the Department of Molecular and Cellular Physiology at Stanford University. She was appointed to the Biology Faculty at the California Institute of Technology (Caltech) in 1993 and stayed there until 2009. In 2009, she moved to Frankfurt, Germany to found the Department of Synaptic Plasticity in Max Planck Institute for Brain Research.
In 1997 Erin Schuman was appointed Investigator at the Howard Hughes Medical Institute (HHMI). She received several awards and grants, including the Pew Scholars Award, the Beckman Young Investigator Award, and an Alfred P. Sloan Fellowship. In 1995, she was named as the American Association of University Women’s Emerging Scholar. In 2013, she gave the Cruikshank Lecture at the GRC on Dendrites and received the Hodgkin Huxley Katz Prize Lecture by the Physiological Society (UK).
Dr Morgan Sheng, Genentech, South San Francisco, USABehavioral and synaptic plasticity deficits in mice lacking caspase-3
NMDA receptor-dependent synaptic modifications such as long-term potentiation (LTP) and long-term depression (LTD) are essential for brain development and function. LTD and synapse elimination are natural processes that sculpt the developing brain, akin to programmed cell death (also termed apoptosis). NMDA receptor-dependent LTD and synapse elimination share common molecular mechanisms with apoptosis. Stimulation of the mitochondrial (or intrinsic) pathway of apoptosis, which culminates in caspase-3 activation, is required for LTD and AMPA receptor internalization in hippocampal neurons. This pathway is activated transiently, moderately and locally in the vicinity of synapses to effect synapse depression without killing the cell. Local activation of the mitochondrial apoptosis pathway in dendrites of neurons by an optogenetic approach is sufficient to cause local loss of dendritic spines and retraction of dendrite branches, without neuronal death. Thus apoptotic mechanisms can sculpt the morphology of neurons in localized fashion. The ubiquitin proteasome system is important for spatially limiting the activation of the apoptotic mechanisms and preventing cell death. Similar “synaptic apoptosis” mechanisms are co-opted by amyloid-beta to impair synaptic plasticity, which could contribute to the synapse dysfunction and loss of Alzheimer’s disease. Mice lacking caspase-3 have normal LTP but show deficits in LTD and homeostatic synaptic plasticity (synaptic downscaling during heightened activity). Behaviorally, caspase-3 knockout mice show specific defects in attention, habituation to novel stimuli and cognitive flexibility.
Morgan Sheng is currently Vice-President of Neuroscience, Genentech Inc, South San Francisco, USA, where he heads Neuroscience research and drug discovery. Previously, from 2001-2008, Dr Sheng was the Menicon Professor of Neuroscience and HHMI Investigator at the Massachusetts Institute of Technology, Cambridge, USA, and before that, he was a member of the faculty of the Department of Neurobiology at Massachusetts General Hospital, Harvard Medical School, Boston. Dr Sheng was trained in physiology at Oxford University (BA), medicine at London University (MBBS), molecular cell biology at Harvard University (PhD), and neuroscience at UC San Francisco (postdoc). He has been the recipient of the Young Investigator Award of the Society for Neuroscience, and the Fondation IPSEN award for Neuronal Plasticity. He is an elected Fellow of The Royal Society (UK), Fellow of the Academy of Medical Sciences (UK), and Fellow of the American Association for the Advancement of Science.
Professor Susumu Tonegawa, RIKEN-MIT Center at the Picower Institute, MIT, USAEngrams for Genuine and False Memories
An important question in neuroscience is how a distinct memory is formed and stored in the brain. Recent studies conducted with cell ablation techniques suggest that defined populations of neurons carry a specific memory trace, or engram. However, these provide “loss of function” evidence. “The final test of any hypothesis concerning memory engrams must be a mimicry experiment in which apparent memory is manifested artificially without the usual requirement for sensory information…” (Martin and Morris, 2002). To this end, we have shown that in mice, the optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behavior in the context not used for conditioning. These data combined with those from various control experiments demonstrated that a sparse but specific ensemble of hippocampal neurons bear the engram of a specific memory, and its activation is sufficient for the recall of that memory. While memories are usually good guides for behaviors, they can also be quite unreliable and have serious consequences in legal settings. However, the lack of relevant animal models has largely hindered our understanding of false memory formation. The development of the technology to identify and activate memory engram-bearing cells created a way to investigate neural mechanisms underlying false memories. Specifically, we hypothesized that a false memory could be generated by an association of an internally activated memory of a previous experience with a concurrently delivered external stimulus of high valence. We found such a false memory is indeed formed in mouse when the contextual engram formed previously is artificially activated subsequently by optogenetic stimulation while the footshock is delivered in a context that is distinct of the original context.
Susumu Tonegawa received his PhD. from UCSD. He then undertook postdoctoral work at the Salk Institute in San Diego, before working at the Basel Institute for Immunology in Basel, Switzerland, where he performed his landmark immunology experiments. Tonegawa won the Nobel Prize for Physiology or Medicine in 1987 for “his discovery of the genetic principle for generation of antibody diversity.” He has since continued to make important contributions but in an entirely different field: neuroscience. Using advanced techniques of gene manipulation, Tonegawa is now unraveling the molecular, cellular and neural circuit mechanisms that underlie learning and memory. His studies have broad implications for psychiatric and neurologic diseases. Tonegawa is currently Picower Professor of Biology and Neuroscience at the Massachusetts Institute of Technology (MIT) and the Director of the RIKEN-MIT Center for Neural Circuit Genetics at MIT as well as the Director of RIKEN Brain Science Institute.
Professor Todd Sacktor, SUNY Downstate Medical Centre, USAPKMzeta and memory persistence
Most molecular targets for the manipulation of memory focus on the signaling events that initiate memory formation during the brief time window of cellular memory consolidation that lasts only hours after learning. Targets for maintaining the storage of long-term memory for days to weeks after consolidation have been unknown. Recently, the persistently active atypical PKC isoform, PKMzeta, has been identified as a potential component of the molecular mechanism maintaining LTP. Based upon this work, studies on PKMzeta have provided the first clues to the molecular mechanisms of how long-term memories are stored. Pharmacological or genetic manipulations decreasing PKMzeta activity disrupt both new and established long-term memories, whereas increasing PKMzeta enhances both new and established memories. After memory consolidation, increases of PKMzeta persist within specific circuits of the brain for weeks. Thus, by targeting PKMzeta, long-term memories can traced, erased, and enhanced.
Todd C. Sacktor received an A.B. from Harvard College in 1978, and an M.D. from the Albert Einstein College of Medicine in 1982. After a residency in neurology at Columbia Presbyterian Medical Center, he studied the role of protein kinase C (PKC) in short-term memory in the model system Aplysia californica, under the tutelage of Dr. James H. Schwartz, at the Center for Neurobiology and Behavior, directed by Dr. Eric R. Kandel. In his own laboratory at SUNY Downstate Medical Center in 1990, he discovered a brain-specific PKC isoform, PKMzeta. Together with colleagues, his lab demonstrated that PKMzeta was both necessary and sufficient for maintaining long-term potentiation (LTP) and storing the long-term memory trace.
Professor Yu Tian Wang, University of British Columbia, USACritical roles of AMPAR endocytosis in LTP and memory decay
Hippocampal long-term potentiation, one of the most well characterized forms of synaptic plasticity, can be temporally and mechanistically classified into early phase, decaying LTP (E-LTP) and late phase, non-decaying LTP (L-LTP). While the non-decaying nature of L-LTP is thought to be dependent on protein synthesis and contributes to memory maintenance, little is known about the mechanisms and roles of the decaying E-LTP. We hypothesize that the decaying of E-LTP is mediated by an active process involving homeostatic endocytosis of postsynaptic -amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid glutamate receptors (AMPARs) at the potentiated synapses during E-LTP and that during the L-LTP, there is a transcription and translation of a PKM-like molecule that tonically inhibits this homeostatic AMPAR endocytosis, thereby preventing LTP from decaying. In supporting this hypothesis, we demonstrate that inhibiting endocytosis of postsynaptic AMPARs prevents the decay of E-LTP, thereby converting it into L-LTP. Conversely, releasing AMPAR endocytosis by inhibiting a PKM-like molecule with ZIP peptide causes L-LTP to decay, thereby converting it into E-LTP. Moreover, we found that in a transgenic mouse model of Alzheimer's disease, inhibition of AMPAR endocytosis is able to rescue the L-LTP, prolong memory retention in normal animals, and reduce memory loss. These results strongly suggest that the decay of E-LTP is mediated by an active process involving facilitated AMPAR endocytosis, and inhibiting this process can prolong the longevity of LTP as well as memory under both physiological and pathological conditions.
Dr Yu Tian Wang, Professor and the holder of the Heart and Stroke Foundation of B.C. & Yukon Chair in Stroke Research in the Department of Medicine and the Brain Research Centre at the University of British Columbia, obtained his PhD. in Neuroscience in 1992 from Memorial University, Canada and both B.M. (Medicine) in 1982 and M.Sc. (Physiology) in 1985 from Shandong University Medical School in China. He worked in Department of Laboratory Medicine and Pathobiology at University of Toronto as an Assistant Professor, and then an Associate Professor between 1994 and 2001. He was also a Howard Hughes Medical Institute International Scholar between 2001-2011 and has been a Fellow of the Academy of Sciences of Royal Society of Canada since 2006. Dr Wang’s research focuses on understanding the molecular mechanisms responsible for regulating the function and intracellular trafficking of glutamate and GABA receptors in brain function and dysfunction.
Professor Bong-Kiun Kaang, Seoul National University, KoreaImpaired long-term potentiation and depression in a mouse model of autism
Altered synaptic function is implicated in the pathogenesis of autism and other synaptopathies. Recently, one de novo SHANK2 microdeletion was found in an autism patient. To understand how this microdeletion leads to the autistic behaviors, we examined synaptic properties in the hippocampal CA1 synapses of KO mice carrying the same human mutation. We found that NMDA receptor dependent LTP and LTD at CA1 synapses were impaired in Shank2 KO mice. Furthermore, the NMDA/AMPA ratio was reduced significantly relative to WT synapses. We also found that CDPPB (mGluR5 PAM) recovered not only the NMDA/AMPA ratio in hippocampal KOslices, but also restored the impaired LTP and LTD in Shank2 KO brainslices. In summary, we have demonstrated that deletion of Shank2 gene in mice, which is identical to the SHANK2 mutation found in human autism patient, shows a reduction in the NMDA receptor function, suggesting that NMDA receptor function could be an important mechanism underlying the development of autism-like phenotypes.
Bong-Kiun Kaang, Ph.D. isProfessor of neurobiology at College of Natural Sciences, Seoul National University. He joined Seoul National University as a faculty member since 1994. He obtained B.S. at Seoul National University in 1984. He obtained Ph.D. at Columbia University, in 1992 (Supervisor: Eric R. Kandel). He was Postdoctoral Research Fellow at Center for Neurobiology and Behavior, Columbia University during 1992 - 1994. He is interested in how memory is stored and retrieved. In this regard, his research focuses on molecular events underlying synaptic plasticity. Most synapses are known to be plastic and readily modified by various environmental and learning stimuli. A change in synaptic efficacy leads to a functional modification of neural circuit to represent new information as a result of learning. He has used cellular, molecular, electrophysiological and behavioral techniques to understand the mechanisms underlying learning and memory and higher cognitive brain functions using marine snail and rodents as experimental models.
Professor Michael Rowan, Trinity College, Dublin, IrelandAlzheimer’s disease amyloid ß-protein and hippocampal synaptic plasticity in vivo
Prior to the onset of significant neurodegeneration in Alzheimer’s disease, the structural and functional integrity of synapses in mnemonic circuitry is severely compromised. There is extensive evidence that certain assemblies of amyloid-ß protein (Aβ) cause rapid disruption of synaptic plasticity and memory impairment in animals. Recently we found that water soluble extracts of post mortem brains of patients with Alzheimer’s disease that contained Aß dimer aggregates both inhibited LTP and facilitated LTD in the anaesthetized rat hippocampus in vivo. Our data are consistent with the view that metabotropic glutamate 5 receptor-dependent mechanisms are paramount. The importance of cellular prion protein in mediating these effects was also determined using antibodies, including a humanized version. Currently we are examining synaptic plasticity disruption in a transgenic model of amyloidosis longitudinally in freely behaving rats prior to Aß plaque formation. These studies emphasize the potential benefit of targeting synaptic plasticity-disrupting Aß, and associated mechanisms, in the development of novel early therapeutic interventions.
Professor Rowan was awarded his Ph.D. from Trinity College Dublin in 1981. He was appointed to a lectureship in Pharmacology at Trinity College in 1979 and was made a Fellow of Trinity College in 1991. He was appointed to a personal chair in Neuropharmacology in 2007. Professor Rowan’s research has focused on our understanding of the mechanisms underlying the regulation of synaptic plasticity in vivo by Alzheimer’s disease ß-amyloid (Aß), behavioural stress and learning. The first accounts of the inhibition of LTP in the rat hippocampus by Aß peptides were published by his group. His research team continue to study disruptive effects of Aß in collaboration with several groups internationally.
Professor Robert Malinow, University of California, San Diego, USAAD and glutamate receptors
Dr Malinow was born in Argentina and moved to Oregon, USA as a child. He attended college in Portland (Reed College) where he studied Mathematics. He received an M.D. at the New York University School of Medicine in 1984 and PhD at the University of California at Berkeley in 1986. Dr. Malinow conducted postdoctoral research at Yale University School of Medicine in the Department of Physiology and the Department of Molecular and Cellular Physiology at Stanford University under the guidance of Dr Richard Tsien. Dr Malinow was appointed Assistant Professor at the University of Iowa College of Medicine in 1990. He joined the Learning and Memory Center at the Cold Spring Harbor Laboratory in 1993. In 2008 he moved to the Center for Neural Circuits and Behavior at the University of California at San Diego.
Professor Kei Cho, University of Bristol, UKAlzheimer’s disease, tau and LTD: physiological and pathological synaptic plasticity
Alzheimer’s disease (AD) is the leading form of dementia, characterised in its late stages by significant neuronal death linked to plaques of amyloid-β and tangles of tau protein. This devastating disease remains poorly understood and without an efficacious treatment strategy. Evidence from a variety of experimental AD models demonstrates that aberrantly enhanced downscaling of synaptic transmission, and therefore ‘Synaptic Biology’, is pivitol in AD pathogenesis. Specifically, a long-term synaptic plasticity-like mechanism likely lies at the heart of AD pathology. As a prominent form of synaptic plasticity, long-term depression (LTD) is expressed as a controlled deconstruction and elimination of synaptic connections, primarily through the internalization of excitatory receptors and an associated downregulation in synaptic transmission. We have previously shown that a novel signalling pathway, central components of which form the caspase-apoptosis cascade, is critically required for LTD. Our study suggests that caspase-3-mediated cleavage of Akt-1 plays a key role in LTD and AMPAR endocytosis, without inducing apoptosis. We also found that Aβ induces synaptic elimination and aberrant synaptic plasticity in a specific manner, blocking LTP but actually enhancing LTD signals, such as caspase-3 and glycogen synthase kinase-3β (GSK-3β). We now bring these two findings together; given that Akt-1 ordinarily serves to down-regulate GSK-3β activity, the caspase cleavage of Akt-1 leads to the activation of GSK-3β. Very recently, we found that the induction of LTD is associated with the GSK-3β-mediated phosphorylation of tau, another key pathophysiological feature of AD. These observations demonstrate that tau has a critical physiological function in LTD. Therefore, the primary importance of understanding the molecular details of these LTD-signal pathways is to determine the interplay between physiology and pathophysiology in the brain.
Professor Kei Cho is Chair and Professor of Neuroscience in the School of Clinical Sciences, Faculty of Medicine and Dentistry, at the University of Bristol, UK. He is a Wolfson Research Merit Award of the Royal Society London Holder (2011) and Vice-President of the London Health Forum 2013. Cho has pioneered the understanding of the molecular mechanisms of long-term depression (LTD) in the perirhinal cortex and hippocampus. Cho has developed his expertise in synaptic biology, with an emphasis on its relevance to neurodegenerative disease. Recently, Cho and his collaborators made the surprising discovery that caspases play non-apoptotic roles in neurons and postulated that caspase-mediated cleavage of Akt-1 formed part of a hippocampal LTD mechanism, ultimately leading to AMPAR endocytosis (Cell (2010) 141, 859-871). Cho began to formalize the importance of the caspase-Akt-1-GSK-3β cascade (CAG cascade) in amyloid beta-mediated pathophysiological synaptic dysfunction in the hippocampus (Nat Neurosci (2011) 14, 545-547). Cho continues to determine how aberrant forms of LTD (or synaptic elimination) are expressed and what their physiological and pathological significances might be. This has led to the discovery of several putative drug targets for Alzheimer’s disease (AD) treatments and brain ageing.
Professor Min Zhuo, University of Toronto, CanadaLong-term potentiation in the anterior cingulate cortex and chronic pain
Glutamate is the primary excitatory transmitter of sensory transmission and perception in the central nervous system. Painful or noxious stimuli from the periphery ‘teach’ humans and animals to avoid potentially dangerous objects or environments; while tissue injury itself causes unnecessary chronic pain that can even last for long-periods of time. Conventional pain medicines often fail to control chronic pain. Recent neurobiological studies suggest that synaptic plasticity taking place in sensory pathways, from spinal dorsal horn to cortical areas, contributes to chronic pain. Injuries trigger long-term potentiation of synaptic transmission in the spinal cord dorsal horn and anterior cingulate cortex (ACC), and such persistent potentiation does not require continuous neuronal activity from the periphery. At the synaptic level, potentiation of excitatory transmission caused by injuries may be mediated by the enhancement of glutamate release from presynaptic terminals and potentiated postsynaptic responses of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptors. Preventing, ‘erasing’, or reducing such potentiation may serve as a new mechanism to inhibit chronic pain in patients in the future.
Dr Zhuois a pain neuroscientist. He was born in Xiapu (a fishing village in China), and, at the age of 16, he was admitted to the University of Science and Technology, graduating in 1985. At Iowa, he finished PhD in Gebhart’s laboratory. In 1992, Zhuo joined Kandel’s laboratory in Columbia where he showed CO-cGMP as key messengers for presynaptic LTP. In 1995, Zhuo spent one year in Tsien’s laboratory in Stanford. In 1996, Zhuo moved to Washington University at St Louis and focused on pain plasticity at the spinal cord and cortex. He showed that ‘smart’ mice suffered more pain, GluN2B and AC1 are novel therapeutic targets for treating chronic pain. In 2003, he moved to University of Toronto, and identified NB001 as a selective inhibitor for AC1. He co-established two online journals, Molecular Pain and Brain. In 2009, he was elected to Fellow of Royal Society of Canada.
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Watch videos of past events.
Most of our talks are free and open to the public.
We host major conferences for leading scientists.
Explore our annual science exhibition
Contact the events team.