Long-term potentiation – 50 years on

Welcome remarks

Professor Tim Bliss FRS

The Francis Crick Institute, UK

Professor Tim Bliss FRS

The Francis Crick Institute, UK

Tim Bliss FRS joined the scientific staff at the National Institute for Medical Research in Mill Hill, London in 1967. He was head of the Division of Neuroscience from 1988 till his retirement in 2006. He and his Norwegian colleague Terje Lømo published the first detailed account of LTP in 1973.  He continued to work on the mechanisms of LTP and its contribution to the synaptic basis of learning and memory throughout his career.  With colleagues he is currently preparing a second edition of The Hippocampus Book, a comprehensive multi-authored book on all things hippocampal. 

Modest success in clinical trials of amyloid β-lowering agents for Alzheimer’s disease (AD) make the identification of alternative candidate molecular targets for therapy a major priority. However, a limited understanding of molecular pathways mediating the effects of amyloid β on synaptic and cognitive function make this challenging. Today I will discuss how oligomeric amyloid β (Aβo) enhances presynaptic CaV2.1 voltage-gated Ca2+ channel activity via a multi- step pathway that ultimately potentiates action potential-evoked synaptic vesicle exocytosis. Normalization of presynaptic function by pharmacological CaV2.1 inhibition or genetic CaV2.1 haploinsufficiency rescues Aβo-induced loss of dendritic spines and synaptic long-term potentiation ex vivo, and prevents spine loss, memory deficits and premature mortality in vivo. The results suggest that enhanced CaV2.1-driven presynaptic exocytosis plays a critical role in the synaptic and cognitive decline seen in AD.

Professor Nigel Emptage

University of Oxford, UK

Professor Nigel Emptage

University of Oxford, UK

Professor Nigel Emptage is Professor of Synaptic Neuropharmacology at the University of Oxford and Sub-Rector, Lincoln College Oxford. He has had the great privilege to study and work in some exceptional laboratories: Professor Malcolm Burrows, Cambridge, where he received his PhD; Professor Tom Carew, Yale, where he held a SERC-NATO Fellowship; and Professor Tim Bliss, NIMR. His group are interested in synaptic transmission. They wish to understand the way in which synapses behave when functioning normally but also how they perform during memory formation or change when struck by diseases such as Alzheimer’s. The questions the group ask are made possible by their experimental approach, the central tenet of which is that they visualise functioning synapses in living tissue both in vitro and in vivo.

The spatio-temporal organization of neurotransmitter receptors in the postsynaptic membrane is a fundamental determinant of synaptic transmission and thus information processing by the brain. Ionotropic AMPA glutamate receptors (AMPAR) mediate fast excitatory synaptic transmission in the central nervous system. Using a combination of high resolution single molecule superresolution imaging and tracking techniques, we have established that AMPARs are not all stable in the synapse as thought initially, but in large part undergo continuous entry and exit to and from the post-synaptic density through lateral diffusion. The other fraction of AMPAR are highly concentrated inside synapses into a few clusters of around seventy nanometers. These results have opened the new possibility that glutamatergic synaptic transmission is controlled by the regulation at the nanometer scale of the position and composition of these highly concentrated nanodomains. The dynamic exchange of AMPAR within the PSD and between synaptic and extrasynaptic sites is highly regulated by neuronal activity. Using methods to exogenously control AMPAR surface diffusion, we have demonstrated that AMPAR activity-dependent diffusion-trapping from extrasynaptic to synaptic sites directly controls the establishment of long term synaptic plasticity. We have also demonstrated that AMPAR conformation strongly impacts their mobility, desensitized receptors being more mobile than naïve ones. This property likely explains how post-synaptic AMPAR receptor mobility can regulate short term synaptic plasticity, a feature previously ascribed to pre-synaptic mechanisms. We will now present a series of new experiments that decipher the respective contributions of transmitter release, AMPAR desensitization and surface diffusion in the control of high frequency dependent short term plasticity. Our data indicate that AMPAR surface diffusion is not only important for the expression of synaptic potentiation but also for frequency dependent information processing by synapses. 

Dr Daniel Choquet

CNRS, University of Bordeaux, France

Dr Daniel Choquet

CNRS, University of Bordeaux, France

Daniel Choquet is a CNRS research director. He graduated from Ecole Centrale (Paris, France) in 1984 and completed his PhD in the lab of Henri Korn at the Pasteur Institute (Paris), studying ion channels in lymphocytes. He did a post-doctoral/sabbatical at Duke University (North Carolina, USA) in the laboratory of Michael Sheetz where he studied the regulation of integrin-cytoskeletal linkage by force. He setup his group in Bordeaux (France) at the Institute for Neuroscience and launched an interdisciplinary program on the combination of physiology, cell and chemical biology and high resolution imaging to study the functional role of the dynamic organization of neurotransmitter receptors in synaptic transmission. He is heading the Institute for Interdisciplinary Neuroscience and the Bordeaux Imaging Center core. He is also the director of the center of excellence BRAIN. He is a Member of the French Science Academy and has been awarded three consecutive ERC advanced grants.

High frequency activation of excitatory glutamatergic synapses induces two forms of N-methyl-D-aspartate (NMDA) receptor dependent long-lasting potentiation (LLP), which are somewhat counterintuitively referred to as short-term potentiation (STP) and long-term potentiation (LTP). However, the longevity of both STP and LTP is not absolute but depends on the reference frame and actions of the observer, whose measurement of STP and LTP introduces uncertainty in the outcome of the experiments by affecting the duration of plasticity.

STP and LTP are frequently co-induced and co-expressed in adult hippocampal synapses. During such experiments potentiation of synaptic responses is probed by using low frequency presynaptic stimulation (e.g. 0.017 to 0.13 Hz), which retains the stability of baseline postsynaptic responses. After the induction of potentiation, the sensitivity of the responses to synaptic stimulation changes, and the decay of STP – or its depotentiation – happens readily when probed with baseline stimulation frequencies that do not affect LTP. During absence of the stimulation the levels of both STP and LTP are maintained over time, until the potentiated synaptic responses are probed again by stimulation. The depotentiation of LTP requires higher frequencies of stimulation than STP (e.g. 1-2 Hz), leading to the erasure of both types of synaptic plasticity.

During the past 50 years LTP has established itself as a reputable correlate of the long-lasting memory storage whilst the idea that STP could be the synaptic mechanism behind the storage of the shorter-lasting memories has been slowly gaining traction over the past 20 years. During this talk I will review some of the evidence that STP is a form of LLP with a unique pharmacological and functional profile and will discuss some of our unpublished data regarding its decay.

Professor Arturas Volianskis

Cardiff University, UK

Professor Arturas Volianskis

Cardiff University, UK

Arturas Volianskis is Senior Lecturer in Neuroscience at Cardiff University, where he studies pharmacology and physiology of synaptic transmission, neurotransmitter receptor function and synaptic plasticity; in particular short-term potentiation (STP) and long-term potentiation (LTP). Arturas holds Humanities degree (BA) from Vytautas Magnus University in Kaunas, Lithuania and research degrees in Philosophy (MA) and Medicine (PhD) from the University of Aarhus, Denmark. From 1999 to 2006 Arturas first trained as an electrophysiologist, and later worked as a postdoc in Professor Morten S Jensen lab in Aarhus. In 2006 he joined the research groups of Professors Graham L Collingridge and David E Jane at the University of Bristol, where he contributed to the development of new pharmacological tools and researched synaptic plasticity. In 2015 Arturas was appointed Lecturer in Neuroscience, at Queen Mary University in London and in 2021 he moved to Cardiff University.

Synapses form trillions of connections in the brain, and synapse growth and retraction are vital for learning. Long-term potentiation (LTP) and long-term depression (LTD) are cellular mechanisms of learning that modify synapses. Three-dimensional reconstruction from serial section electron microscopy reveals three distinct pre to postsynaptic arrangements: strong active zones (AZs) with tightly docked vesicles, weak AZs with loose or nondocked vesicles, and nascent zones (NZs) with a postsynaptic density but no presynaptic vesicles. One LTP induction can temporarily saturate subsequent LTP that recovers with time. At the onset of LTP, vesicles are recruited to NZs, converting them to AZs. During recovery (1-4 hours), new NZs form, especially on spines where AZs were most enlarged by LTP. These sentinel spines contain smooth endoplasmic reticulum (a local resource regulating calcium, lipids, and proteins), and after recovery clusters of resource poor spines surround sentinel spines. We propose a model where NZ plasticity provides synapse specific AZ expansion during LTP and elimination during LTD. Spine clusters become functionally engaged during LTP to enhance local circuits, or disassembled during LTD. Thus, spacing episodes of LTP or LTD protect recently formed memories from ongoing plasticity and may account for the advantage of spaced over massed learning.

Dr Kristen Harris

University of Texas at Austin, USA

Dr Kristen Harris

University of Texas at Austin, USA

Kristen Harris rose through the ranks to Associate Professor at Harvard and was recruited as a tenured Professor first to Boston University, then as a Georgia Research Alliance Eminent Scholar at the Medical College of Georgia, and for the past 15 years she has been a leader in the Department of Neuroscience and Center for Learning and Memory at the University of Texas at Austin. She is renowned for her work on synapse structure and function having pioneered three-dimensional reconstruction from serial section electron microscopy. In addition to the more than 125 publications, she also shares her data and tools (synapseweb.clm.utexas.edu), which are resources used worldwide. She has been the recipient of the Sloan Research Fellowship, Javits Merit Award, Brain Research Foundation Fellowship, and many others. Among other grants, she is currently the lead PI on a large NSF NeuroNex grant with 26 co-PIs throughout the world to understand synaptic weights in neural circuits. She is known for innovative teaching, international seminars, and her service on study sections and scientific advisory boards (Janelia, Max Planck Institute for Brain Research, The Allen Institute for Brain Research). 

Discovering LTP has been the most prominent empirical validation of the basic principles of memory formation put forward by Hebb. Generating a memory trace in neural networks is thought to involve changes in the synaptic connectivity strength and in cell intrinsic excitability, but how this process unfolds in the living brain has remained elusive. We have advanced a multiplexed imaging method involving fluorescent indicators of glutamate and Ca2+, to monitor changes in the release reliability at individual excitatory synapses in vivo. In the mouse barrel cortex, we thus detected increased fidelity coupled with reduced excitation of thalamocortical connections that undergo whisker-stimulation induced LTP. High-speed high-resolution imaging also revealed that whisker stimuli trigger synaptic activity that generates extrasynaptic glutamate transients reaching the bulk of synapses in the target cortical area. Our findings help to appreciate some basic plasticity traits of the synaptic connectome while suggesting that a significant component of excitatory signalling in the living brain could be volume-transmitted by glutamate escaping the synaptic clefts.

Professor Dmitri Rusakov

University College London, UK

Professor Dmitri Rusakov

University College London, UK

Dmitri Rusakov is a Professor of Neuroscience (since 2007) at UCL Queen Square Institute of Neurology. Following his MSc in Physics, he obtained a PhD in Neurobiology-Biophysics from Bogomoletz Institute of Physiology, NAS Kiev. He underwent postdoctoral training at the Open University and the MRC Institute for Medical Research where he started an independent group in 1998, before moving to UCL in 2000. Dmitri set up the UK’s first two-photon excitation-uncaging microscope integrated with patch-clamp, and developed multiplexed time-resolved fluorescence microscopy for intact-brain imaging. His research focuses on the physiology and biophysics of synaptic transmission, astroglia, and neural microcircuits - in the quest to understand the principles of information processing in the brain. He obtained competitive research awards including an MRC Career Development Award, Wellcome Trust Senior Fellowship (twice) and Principal Fellowship (twice), as well as an ERC Advanced Grant. Elected a Member of Academia Europaea in 2012.

Two separable yet interactive cellular activity features have been associated with neuronal populations implicated in memory formation. The first feature concerns the induction of synaptic plasticity at synapses that receive characteristic stimuli to trigger postsynaptic NMDA receptor signaling during such cognitive events. The second relates to activity-dependent gene expression via a synapse-to-nucleus signaling mediated mainly by a transcription factor CREB. Synaptic inputs locally trigger neuroplastic signaling at the stimulated synapses while also turning on activity-dependent mechanisms linking synapses and the nucleus, which control long-term memory and late-phase long-term plasticity. Single synapse LTP recording of glutamate receptor lateral diffusion showed that trafficking of Arc to weak synapses, through an inverse synaptic tagging mechanism during the late phase of long-term plasticity, underlies late-phase heterosynaptic depression. Thus, Arc is a component of a heterosynaptically expressed negative synaptic engram that facilitates long-term maintenance of strong-to-weak contrast of synaptic weights on a stimulated dendrite. These findings pave the way toward a better understanding of the neuropathological significance of disrupting learning-associated transcriptional signaling in disorders such as schizophrenia, autism, and intellectual disability.

Professor Haruhiko Bito

University of Tokyo, Japan

Professor Haruhiko Bito

University of Tokyo, Japan

Haruhiko Bito is a Professor and Chair of Neurochemistry at the University of Tokyo. He graduated from the University of Tokyo with an MD and a PhD in Biochemistry in 1993. After postdoctoral training at Stanford University as an HFSP Fellow, he started his laboratory in Pharmacology at Kyoto University in 1997 before moving to head the Department of Neurochemistry at the University of Tokyo in 2003. Dr Bito has deciphered novel functions of many members of the CaMK family, and elucidated the bidirectional neuronal signaling between the synapses and the nucleus, essential for late-phase plasticity and long-term memory. Dr Bito has also designed powerful molecular tools (E-SARE synthetic activity-dependent enhancer and next-generation Ca2+ indicators XCaMPs) that help capture and measure neuronal ensemble activity critical for cognition. He received the Young Investigator Awards from the Japanese Societies for Pharmacology (2003) and Biochemistry (2004), the Tsukahara Award (2011), AND Investigator Award (Molecular Brain, 2015), and the Setsuro Ebashi Award (2020).

The hippocampus plays an integral role in episodic memory, primarily through neurons in the CA1 subfield. Beyond the well-established canonical circuitry, the CA2 region is implicated in social memory. CA2 neurons also display unique biochemical properties and are more resistant to plasticity. Our earlier studies observed metaplastic effects of neuromodulators that permit plasticity in CA2 neurons. Notably, there are monosynaptic connections from CA2 that innervate CA1, the functional relevance of which remains relatively unknown. Our study aims to investigate how these CA2-CA1 connections can modulate the maintenance of functional plasticity models, such as long-term potentiation (LTP) and long-term depression (LTD), within the Schaffer collateral (SC)-CA1 synapses. Subthreshold stimulation of SC-CA1 synapses revealed an early form of LTP (early-LTP) but not the persistent late form (late-LTP). However, when 'primed' by the activation of CA2, SC-CA1 synapses exhibit protein synthesis-dependent late-LTP upon subthreshold stimulation within a temporal window that also promotes associative plasticity, such as synaptic tagging and capture (STC). Moreover, CA2 'priming' does not disrupt the persistence of late forms of LTD when SC-CA1 synapses are stimulated by strong low-frequency stimulation. In fact, weak low-frequency stimulation can promote protein synthesis-dependent late-LTD in CA2-primed SC-CA1 synapses. Lastly, we established a behavioural model wherein social novelty, which activates CA2, can enhance the persistence of CA1-dependent memory via the weak inhibitory avoidance task. Combining a chemogenetics approach with behavioural assays also confirmed the role of CA2 in enhancing CA1-dependent memory. This set of results demonstrates that CA2 connections onto CA1 can influence the synaptic plasticity of CA1, suggesting possible implications for how social behavioral states can modulate the persistence of memory.

Associate Professor Saji Kumar Sreedharan

National University of Singapore, Singapore

Associate Professor Saji Kumar Sreedharan

National University of Singapore, Singapore

Dr Sajikumar obtained his PhD from the Leibniz Institute for Neurobiology in Magdeburg, Germany, in 2005, focusing on the study of memory mechanisms. He conducted postdoctoral research and served as a group leader at the Technical University in Braunschweig, Germany, investigating the role of metaplasticity in associative memory at the cellular level. His research on synaptic tagging and capture has uncovered crucial mechanisms and molecules involved in associative plasticity and memory formation.

Since 2012, Dr Sajikumar has been a faculty member at the Department of Physiology and Research Director (since 2021) of the Healthy Longevity Translational Research Programme at the Yong Loo Lin School of Medicine, National University of Singapore. His research primarily revolves around aging, neurodegeneration, synaptic tagging and capture (STC) as a mechanism for long-term memory storage, and metaplasticity for enhancing memory in aging and neurodegenerative neural networks.

Dr Sajikumar serves on the editorial boards of esteemed international journals, including Neurobiology of Learning and Memory, Experimental Brain Research, Frontiers in Molecular Neuroscience, and Oxford Open Neuroscience. He has been recognized with awards such as the Singapore Neuroscience Association Young Investigator Award (2017), Faculty Research Excellence Award (2017), and Graduate Mentor Award (2021) from the National University of Singapore.

His research has received support from renowned funding bodies, including the Alexander von Humboldt Foundation, Deutsche Forschungsgemeinschaft, National Medical Research Council, Ministry of Education in Singapore, and National Institute of Aging (NIA), NIH, USA.

Long-term potentiation (LTP) at hippocampal CA3-CA1 synapses includes at least two mechanistically distinct forms of NMDAR-dependent synaptic potentiation, based on their independence (LTP1) or dependence on de novo protein synthesis (LTP2). Prior work established that calcium-permeable AMPAR (CP-AMPAR) activation is specifically required for LTP2. The current study aimed to address the role of intracellular Ca2+ stores in LTP and a form of heterosynaptic metaplasticity known as synaptic tagging and capture (STC).  The effects of inhibitory concentrations of ryanodine and cyclopiazonic acid (CPA), were examined on LTP induced by three distinct induction protocols. A single episode of theta-burst stimulation (TBS) and three episodes of compressed TBS (10 s interval between episodes), readily induced LTP1 in the presence of these compounds. However, LTP2 (induced by three episodes of spaced TBS (10 min between episodes) was inhibited when CICR was blocked. STC was similarly sensitive to CICR blockade. CICR is therefore specifically required for the forms of synaptic plasticity that require the activation of CP-AMPARs, PKA and de novo protein synthesis. In addition, to investigate the relationship between functional and structural plasticity, simultaneous field potential recordings and two-photon imaging were carried out in acute hippocampus slices from adult mice expressing Thy1-EGFP. Using FM 4-64 we were able to identify active (FM+) and non-active (FM-) synapses. We observed that the delivery of sTBS, but not cTBS, led to a substantial and sustained increase in spine size at FM+ synapses but not FM- ones. Interestingly, the increase in spine size induced by sTBS was blocked by IEM-1460, a CP-AMPAR inhibitor, as well as by D-AP5 and anisomycin. Together these findings demonstrate the involvement of calcium stores in LTP2 and the requirement of CP-AMPARs in both functional and structural plasticity.  

Dr Laura Koek

Lunenfeld - Tanenbaum Research Institute, Canada

Dr Laura Koek

Lunenfeld - Tanenbaum Research Institute, Canada

Dr. Laura Koek is a postdoctoral research fellow in the lab of Professor Graham Collingridge at the Lunenfeld - Tanenbaum Research Institute in Toronto, Canada. She completed her BSc in Neuroscience at the University of Toronto in 2018 and obtained her PhD in Physiology from the University of Toronto in 2023. Her research uses two-photon imaging, electrophysiology and pharmacology to explore the roles of different intracellular calcium stores in structural and functional synaptic plasticity in the hippocampus.

Hippocampal long-term potentiation (LTP) and long-term depression (LTD) comprise the principal cellular mechanisms that fulfill widely accepted criteria for the physiological correlates of learning and memory. Over the last few decades, both correlative and concomitant experimental evidence has accumulated that indicates that hippocampal LTP enables the acquisition of associative and spatial memories, whereas LTD supports the retention of information about spatial content, and contributes to information updating and the stabilisation of acquired spatial representations. Recordings of hippocampal field potentials during spatial learning, coupled with the scrutiny of experience-dependent somatic immediate early gene expression as a biomarker of localised information encoding, has revealed that LTP that results from spatial learning recruits neuronal networks across all hippocampal subfields whereas LTD is expressed in a subcompartment-specific manner relative to the kind of spatial content information that is acquired, or updated. This interplay of LTP and LTD during memory acquisition and updating prevents generalisation of spatial memory and supports the reliable disambiguation of similar representations.

Professor Denise Manahan-Vaughan

R.U.Bochum, Germany

Professor Denise Manahan-Vaughan

R.U.Bochum, Germany

Denise Manahan-Vaughan is a neurophysiologist, neuroscientist and head of the Department of Neurophysiology within the Medical Faculty of the Ruhr University Bochum (www.rub.de/neurophys). She is also director of the Institute of Physiology, Dean of Studies of the International Graduate School of Neuroscience (www.rub.de/igsn), and speaker of the Research Department of Neuroscience of the Ruhr University (http://www.rd.ruhr-uni-bochum.de/neuro/index.html.en). In 2021 she was elected as Vice-President  for structure, strategy and planning of Ruhr University Bochum. In July 2022 she was elected to the Leopoldina German National Academy of Sciences (https://www.leopoldina.org/en/).
Her research focusses  on understanding the relationship between hippocampal and cortical synaptic plasticity and long-term associative and spatial memory. She does this by combining a variety of in vivo electrophysiological approaches in rodents with techniques such as optogenetics, fMRI, molecular biology, behavioural paradigms and transgenic animal models. She has published over 180 peer-reviewed papers in these areas.

Understanding how the brain uses information is a fundamental goal of neuroscience. Several human disorders (ranging from autism spectrum disorder to PTSD to Alzheimer’s disease) may stem from disrupted information processing. Therefore, this basic knowledge is not only critical for understanding normal brain function, but also vital for the development of new treatment strategies for these disorders. Memory may be defined as the retention over time of internal representations gained through experience, and the capacity to reconstruct these representations at later times. Long-lasting physical brain changes (‘engrams’) are thought to encode these internal representations. The concept of a physical memory trace likely originated in ancient Greece, although it wasn’t until 1904 that Richard Semon first coined the term ‘engram’. Despite its long history, finding a specific engram has been challenging, likely because an engram is encoded at multiple levels (epigenetic, synaptic, cell assembly). My lab is interested in understanding how specific neurons are recruited or allocated to an engram, and how neuronal membership in an engram may change over time or with new experience. Here I will describe data in our efforts to understand memories in mice.

Professor Sheena Josselyn

Hospital for Sick Children, Canada

Professor Sheena Josselyn

Hospital for Sick Children, Canada

Sheena Josselyn is a Senior Scientist at The Hospital for Sick Children (SickKids) and a Professor in the departments of Psychology and Physiology at the University of Toronto in Canada. Dr. Josselyn holds a Canada Research Chair in Brain Mechanisms underlying Memory, is a Fellow of the Royal Society of Canada and a Fellow of the National Academy of Medicine (US).

Her undergraduate degrees in Psychology and Life Sciences and a Masters degree in Clinical Psychology were granted by Queen’s University in Kingston (Canada). Sheena received a PhD in Neuroscience/Psychology from the University of Toronto with Dr. Franco Vaccarino as her supervisor. She conducted post-doctoral work with Dr. Mike Davis (Yale University) and Dr. Alcino Silva (UCLA).

Dr. Josselyn received numerous awards, including the Innovations in Psychopharmacology Award from the Canadian College of Neuropsychopharmacology (CCNP), the Effron Award from the American College of Neuropsychopharmacology (ACNP) and the Andrew Carnegie Prize in Mind and Brain Sciences.

Dr. Josselyn is interested in understanding how the brain encodes, stores and uses information. Her primary model organism is mice. However, several human disorders (ranging from autism spectrum disorder to Alzheimer’s disease) may stem from disrupted information processing. Therefore, this basic knowledge in mice is not only critical for understanding normal brain function, but also vital for the development of new treatment strategies for these disorders.

 

Commentaries about LTP generally proceed with the implicit assumption that more or less the same physiological effect is being sampled across different experiments. Increasing evidence indicates that this is not the case. Potentiation in CA3-CA1 synapses, the best studied of all LTP cases, is expressed by an expansion of the AMPAR pool and stabilized by adjustments to the spine cytoskeleton. In contrast, the lateral perforant to dentate gyrus connections use a presynaptic, endocannabinoid-dependent form of LTP. Further differentiation comes from work describing sex differences in the substrates for CA1-LTP and in particular a female dependency on synaptic estrogen signaling to stabilize the potentiated state. CA1-LTP undergoes profound changes during puberty with the male threshold for induction decreasing and the female threshold increasing. Relatedly, prepubescent female rodents outperform males on the spatial component of episodic learning. In all, LTPs are differentiated by a minimum of two dimensions, region and sex, with substantial consequences for behavior.

Professor Christine Gall

University of California, Irvine, USA

Professor Christine Gall

University of California, Irvine, USA

TBC