Skip to content
Events

Long-term potentiation: enhancing neuroscience for 40 years - satellite meeting

Event

Starts:

December
042013

09:00

Ends:

December
052013

17:00

Location

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ

Overview

Satellite meeting organised by Professor Graham Collingridge FRS, Professor Tim Bliss FRS and Professor Richard Morris CBE FRS

Attending this event

This is a residential conference, which allows for increased discussion and networking.  It is free to attend, however participants need to cover their accommodation and catering costs if required.

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 after the event

Participants are also encouraged to attend the related scientific discussion meeting Long-term potentiation: enhancing neuroscience for 40 years which immediately precedes this event.

Enquiries: Contact the events team

Event organisers

Select an organiser for more information

Schedule of talks

Session 1

5 talks Show detail Hide detail

JAK/STAT and LTD

Dr Céline Nicolas, University of Bristol, UK

Abstract

The Janus kinase (JAK) / signal transducer and activator of transcription (STAT) pathway is involved in many cellular processes, including cell growth and differentiation. It is activated by various extracellular factors and regulates the transcription of many genes. Of the four JAK isoforms and seven STAT isoforms known, JAK2 and STAT3 are highly expressed in the brain where they are present in the postsynaptic density (PSD).  Using a variety of complementary approaches, we show that the JAK/STAT pathway plays an essential role in the induction of NMDA-receptor dependent long-term depression (NMDAR-LTD) in the hippocampus. However, JAK has no effect on LTP, depotentiation or mGluR-induced LTD.  

We identified JAK2 and STAT3 as the isoforms activated and involved in NMDAR-LTD. We also show that the translocation of STAT3 into the nucleus, which occurs just after the induction of LTD, is not required for the induction of LTD, at least in the first 3 hours after induction. Although the role of STAT3 in the dendrites remains to be identified, it can be concluded that the JAK/STAT pathway has a key role in synaptic plasticity in the CNS.

Show speakers

Left-right asymmetry of hippocampal LTP: implications for memory and memory disorders

Professor Ole Paulsen and Dr Olivia Shipton, University of Cambridge, UK

Abstract

Synaptic plasticity is the best-supported cellular model for learning and memory. It proposes that the timing and/or pattern of neuronal activity lead to long-lasting changes in synaptic weights that carry a memory trace. Using optogenetics we have investigated timing-dependent synaptic plasticity in the mouse hippocampus and found a striking left-right asymmetry of hippocampal plasticity. This talk will present recent data indicating that this left-right asymmetry extends to high-frequency stimulation-induced LTP, long-term memory processing, as well as amyloid beta-induced synaptic changes with relevance to Alzheimer's disease.  These results suggest that hippocampal memory is routed via distinct left-right pathways that are differentially vulnerable in neurodegenerative disease.

Show speakers

Reactivation of plasticity at layer 4 inputs to barrel cortex after loss of competing sensory input

Dr John Isaac, Eli Lilly, UK

Abstract

The adult brain is known to undergo experience-dependent plasticity in response to sensory manipulations or peripheral nerve injuries, both in animals and humans. However, the sites and mechanisms of such plasticity are poorly explored, partly due to a lack of approaches allowing unbiased mapping of plasticity sites that can be combined with studies of underlying mechanisms.  Here, we combined fMRI, and in vivo and in vitro electrophysiology to study plasticity induced by unilateral infraorbital nerve resection in 4-6 week-old rats. BOLD imaging and manganese-enhanced MRI revealed circuit changes in spared layer 4 (L4) barrel cortex in response to unilateral infraorbital nerve resection. In vivo and brain slice electrophysiology showed that the increased activation of L4 could be accounted for by a selective strengthening of the thalamocortical (TC) inputs to L4 stellate cells. This effect was mediated by a specific increase in postsynaptic strength and in the number of functional synapses. We are currently investigating whether a reactivation of long-term synaptic plasticity contributes to these synaptic changes. Our work shows that the TC input is a site for robust plasticity in 4-6 week old rats, after the end of the previously defined critical period for this input.  Thus, TC inputs may represent a major site for adult plasticity challenging the consensus that adult plasticity occurs primarily at cortico-cortical connections.

Show speakers

The role of astroglia in encoding synaptic plasticity

Professor Dmitri Rusakov, University College London, UK

Abstract

Experimental evidence has emerged pointing to diverse and rapid interactions between astroglia and synaptic circuits. We have found that in the hippocampus Ca2+ dependent release of the NMDAR co-agonist D-serine from astrocytes is required for the induction of the classical form of LTP at nearby synapses. However, the underlying principles of intracellular Ca2+ signal integration and transfer by astrocytes remain poorly understood. We combined patch-clamp electrophysiology with two-photon excitation imaging, photo-bleaching monitoring, super-resolution STED microscopy and quantitative 3D EM to characterise quantitatively the fine morphology, intracellular diffusion properties, and Ca2+ homeostasis in common protoplasmic astroglia. Guided by such observations, we have designed a realistic NEURON-style model of the typical passive astrocyte. In parallel, we have developed a life-time fluorescence imaging method to monitor Ca2+ landscapes in astrocytes and in neighbouring synaptic structures with unprecedented sensitivity. Integrating these strategies is helping us to understand cellular machineries that enable astroglia to regulate local synaptic circuitry.

Show speakers

The role of glutamate autoreceptors in plasticity

Professor Nigel Emptage, Oxford University, UK

Abstract

A rise in [Ca2+]i provides the trigger for neurotransmitter release at neuronal boutons. Measurement of the action potential-evoked [Ca2+]i in the boutons of Schaffer collaterals reveals that the trial-by-trial amplitude of the evoked Ca2+ transient is bimodally distributed. We have found that ‘large’ Ca2+ transients occur when presynaptic NMDA receptors are activated following transmitter release, thus they serve as autoreceptors.

Since autoreceptors ‘report’ transmitter release on a trial-by-trial basis we have used this to estimate the probability of release, (pr). We have used this novel estimator to show that pr increases following the induction of LTP providing a further experimental strategy with which it is possible to demonstrate that LTP produces changes at the presynaptic locus.

Recently, we sought to identify a functional role for presynaptic NMDA autoreceptors. We find that they form part of a signalling network at the synapse that regulates pr following the induction of LTP and LTD.

Show speakers

Session 2

4 talks Show detail Hide detail

A role for inhibition in associative fear conditioning

Dr Andreas Lüthi, Friedrich Miescher Institute for Biomedical Research, Switzerland

Abstract

Classical fear conditioning is one of the most powerful models to study the neuronal substrates of associative learning and the mechanisms of memory formation in the mammalian brain. In unraveling the substrates of memory storage in fear conditioning and other learning paradigms, the major focus has been the study of excitatory elements of the brain. However, interneurons are critical components of neuronal networks and inhibition plays an important role in shaping network activity and regulating cellular plasticity, so it is surprising that little is known about the involvement of inhibitory circuits in learning and memory. Over the past few years, we have started to dissect amygdala circuitry with the overall aim to understand the computations that are performed by its elements during associative learning. In my talk, I will show recent data indicating that dis-inhibition mediated by distinct subpopulations of interneurons in amygdala is an important mechanism gating the acquisition of conditioned fear responses.

Show speakers

Leptin regulation of hippocampal synaptic function in health and disease

Dr Jenni Harvey, University of Dundee, UK

Abstract

It is well documented that the hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are widely expressed in the brain and evidence is growing that leptin has the ability to influence many central processes. Indeed, recent studies indicate that leptin has cognitive enhancing properties as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity.  Recent evidence indicates that the ability of leptin to regulate hippocampal synaptic function markedly declines with age. Moreover, aberrant leptin function has been linked to neurodegenerative disorders like Alzheimer’s disease (AD). The evidence supporting a cognitive enhancing role for the hormone leptin and the therapeutic potential of using leptin-based agents to treat age-related neurodegenerative disorders will be discussed.

Show speakers

Long-term depression and synaptic adhesion molecules

Professor Eunjoon Kim, Institute for Basic Science (IBS) and Korea Adv Inst of Sci and Technol (KAIST), Korea

Abstract

Long-term depression (LTD) reduces the functional strength of excitatory synapses through mechanisms that include the removal of AMPA glutamate receptors from the postsynaptic membrane. LTD induction is also known to result in structural changes at excitatory synapses, including the shrinkage of dendritic spines. Synaptic adhesion molecules are thought to contribute to the development, function, and plasticity of neuronal synapses largely through their trans-synaptic adhesions. However, little is known about how synaptic adhesion molecules are altered during LTD. We report here that NGL-3 (netrin-G ligand-3), a postsynaptic adhesion molecule that trans-synaptically interacts with the LAR family of receptor tyrosine phosphatases and intracellularly with the postsynaptic scaffolding protein PSD-95, undergoes a proteolytic cleavage process in an activity dependent manner. NGL-3 cleavage is induced by NMDA treatment in cultured neurons and low frequency stimulation in brain slices and requires the activities of NMDA receptors, matrix metalloproteinases (MMPs), and presenilin/g-secretase. These results suggest that NGL-3 is a novel substrate of MMPs and g-secretase and that NGL-3 cleavage may regulate synaptic adhesion during LTD.

Show speakers

Synaptic plasticity in multiple sclerosis and experimental autoimmune encephalomyelitis

Dr Robert Nisticò, Sapienza University of Rome, CERC – S. Lucia Foundation IRCCS, Rome and EBRI – Rita-Levi Montalcini Foundation, Italy

Abstract

Approximately half of all patients with multiple sclerosis (MS) experience cognitive dysfunction including learning and memory impairment. Recent studies suggest that hippocampal pathology is involved, although the mechanisms underlying these deficits remain poorly understood. Evidence obtained from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests that in the hippocampus of EAE mice long-term potentiation (LTP) is favored over long-term depression (LTD) in response to repetitive synaptic activation, through a mechanism dependent on enhanced IL-1β released from infiltrating lymphocytes or activated microglia. Facilitated LTP during an immune-mediated attack might underlie functional recovery, but also cognitive deficits and excitotoxic neurodegeneration. Having identified that pro-inflammatory cytokines such as IL-1β can influence synaptic function and integrity in early MS, it is hoped that new treatments targeted toward preventing synaptic pathology can be developed.

Show speakers

Session 3

5 talks Show detail Hide detail

Activity dependent restructuring of synaptic inputs

Dr Inbal Israely, Champalimaud Center for the Unknown, Portugal

Abstract

Brain circuits can be structurally rearranged with experience, and synaptic connections can grow and be eliminated even in adult brains.

Many of these changes are long lasting and require the synthesis of new proteins. We are interested in elucidating the learning rules which govern plasticity at individual inputs, both functionally and structurally. We previously demonstrated that spine growth can be cooperative in a protein synthesis dependent manner, and that the simultaneous potentiation of spines induces competition for plasticity, which results in bi-directional changes in spine volume.

The mechanisms which regulate spine shrinkage, however, remain unclear. We examine the structural correlates of a protein synthesis dependent form of synaptic depression, mediated by metabotropic glutamate receptors, and find that in response to the global induction of LTD, a majority of spines shrink or are eliminated. These effects can be observed up to 24 hours following plasticity, and require new protein synthesis. Interestingly, synaptic activity is also needed for spine shrinkage, although not NMDA receptor function. Finally, we use two-photon imaging and glutamate uncaging to stimulate and monitor plasticity at single spines. Therefore, we explore how different forms of activity influence synaptic structure and function, and how information is encoded in a circuit.

Show speakers

Deciphering biochemical information processing during plasticity at single synapses

Professor Haruhiko Bito, University of Tokyo Grad School of Medicine, Japan

Abstract

The nervous system adapts to a fluctuating environment through activity-dependent modulation of neuronal properties such as synaptic plasticity. The direction and extent of such sustainable modulation is determined by the stimulus parameters, suggesting that the biochemical machineries that operate at synapses can readily compute the input information. Ca2+- and calmodulin-dependent kinase II (CaMKII) and calcineurin appear to play key roles in these processes. However, several important theoretical postulates underlying the role of CaMKII and calcineurin during synaptic plasticity—e.g. that CaMKII in spines functions as a high-frequency input detector or that calcineurin is uniquely activated by low-frequency stimulation—remain untested in living neurons. Furthermore, whether and how the information encoded in glutamate release rates at individual synapses can be reliably converted into biochemical activation patterns of these postsynaptic enzymes also remains unexplored. To address these questions, we developed a novel dual FRET imaging platform and recorded CaMKIIα and calcineurin activities in hippocampal neurons, while varying glutamate uncaging frequencies. Five Hz spine glutamate uncaging strongly stimulated calcineurin but not CaMKIIα, with little spine morphological change. In contrast, 20Hz spine glutamate uncaging which induced spine growth activated both CaMKIIα and calcineurin, with distinct spatiotemporal kinetics. Higher temporal resolution recording in the soma revealed that CaMKIIα activity summed supralinearly and sensed both higher frequency and input number, thus acting as an input frequency/number decoder. In contrast, calcineurin activity summated sublinearly with increasing input number and showed little frequency-dependence, thus functioning as an input number counter. Further analyses of the dual recording of Ca2+ transients and downstream enzyme activities revealed that this distinction in fact resulted from the differential decoding of Ca2+ amplitudes vs Ca2+ integrals by CaMKII and calcineurin, respectively. These results provide evidence that CaMKIIα and calcineurin are activated through distinct non-linear Ca2+ decoding mechanisms, and fine-tuned to unique bandwidths, thus computing distinct input variables in an asymmetric, rather than opposing manner. Deciphering critical rules underlying key enzymatic information processing at excitatory synapses enhance our understanding of the temporal and spatial dynamics of molecular memory events underlying synaptic plasticity and learning & memory.

Show speakers

Hebb’s Original Exemplar – plasticity in primary visual cortex enables the detection of novelty

Dr Sam Cooke, Howard Hughes Medical Institute, MIT, USA

Abstract

The cerebral neocortex stores memory. Understanding how this storage occurs requires identification of simple forms of memory that rely upon plasticity within circumscribed areas. As Donald Hebb originally surmised, the primary sensory cortices are likely to be the most experimentally tractable due to their proximity to sensory input, and he therefore chose perceptual learning in primary visual cortex (V1) of the rodent as a central example to expound his theories of how the brain stores information. Here I revisit Hebb’s ideas to consider roles for homo-synaptic plasticity in the modification of vision and behaviour through experience. I will describe a form of visual learning in the mouse that is highly selective for stimulus orientation. The resulting memory, sometimes described as familiarity, is manifested as behavioural habituation and likely serves an important function throughout the animal kingdom, enabling organisms to devote cognition to novel elements of the environment that may carry threat or yield reward. During my talk I will describe results revealing that this form of learning is mediated by input-specific synaptic plasticity within V1 that shares many of the features of canonical long-term potentiation (LTP).

Show speakers

LTP-Induced Neural Network Reorganization: fMRI and electrophysiological evidences

Dr Santiago Canals, Instituo de Neurociencias, Consejo Superior de Investigaciones Científicas y Universidad Miguel Hernández

Abstract

Encoding patterns of synaptic activity into a long-term memory requires molecular and physiological changes at the cellular level but also network interactions. While the cellular mechanisms linking synaptic plasticity to memory have been intensively studied, those regulating network interactions have received less attention. Combining high-resolution fMRI and in vivo electrophysiology we demonstrate a functional remodeling of long-range hippocampal networks induced by long-term potentiation of synaptic plasticity in the perforant pathway. We will present the results of our last experiments investigating the cellular mechanism underlying this synapse-to-network transformation.

Show speakers

Metaplasticity: changing the future of synaptic plasticity

Professor Cliff Abraham, University of Otago, New Zealand

Abstract

Like memory, synaptic plasticity is regulated by many intrinsic and extrinsic variables that affect the neuronal "state". One variable increasingly realised to affect neuronal state is the history of activity in the relevant neural network. We have termed such regulation "metaplasticity". Metaplasticity mechanisms are varied, and likely serve diverse functions. They also range in extent from being synapse-specific to cell-wide. Cell-wide metaplasticity is of particular interest as it can subserve homeostatic control of plasticity thresholds, thereby helping to impart stability to neuronal activity and network function through prevention of runaway synaptic potentiation or depression. The need for such control has been reported in many computational models of plasticity, but experimental demonstrations of such effects are few. Recently we have shown that cell-wide metaplasticity can occur in hippocampal slices in a way that could mediate homeostatic control of synaptic efficacy.  Surprisingly, investigations of its mechanisms have indicated a role for intercellular communication, including a contribution by astrocytes. These findings suggest the possibility that homeostatic metaplasticity mechanisms can function at the network level.

Supported by the New Zealand Marsden Fund, the Health Research Council and the Neurological Foundation of New Zealand.

Show speakers

Session 4

4 talks Show detail Hide detail

Brain plasticity and memory: LTP and beyond

Dr Serge Laroche, Centre of Neuroscience Paris-Sud, CNRS & University Paris-Sud, France

Abstract

A defining characteristic of the brain is its remarkable capacity to undergo activity-dependent functional and structural remodelling via mechanisms of plasticity that form the basis of our capacity to encode and retain memories. The prevailing model of how our brain stores new information about relationships between events or new abstract constructs suggests it resides in activity-driven modifications of synaptic strength and remodelling of neural networks brought about by cellular and molecular changes within the neurons activated during learning. To date, the idea that a form of activity-dependent synaptic plasticity known as long-term potentiation, or LTP, plays a central role in the laying down of memories has received considerable support. Beyond this mechanism of plasticity at the synapse, adult neurogenesis, the birth and growth of new neurons, is another form of neural plasticity which occurs continuously in defined brain regions such as the dentate gyrus of the hippocampus and there is accumulating evidence that this form of neural plasticity also contributes to memory function. Based on work on the role of the transcriptional regulator Zif268, I will review recent evidence which support the idea that in this neurogenic region of the hippocampus, synaptic plasticity and neurogenesis are functionally linked mechanisms of brain plasticity that are essential to store memory memories.

Show speakers

Genetic control of memory circuits

Dr Mark Mayford, Scripps Research Institute, USA

Abstract

When we learn new information we use only a tiny fraction of the neurons in our brain for that particular memory trace.  In this lecture I will discuss recent results from our lab that seek to develop genetic tools to target the sparse subset of neurons associated with a particular specific memory trace. We used a cfos-promoter based system to drive expression of a mutant muscarinic receptor hM3Dq (DREADD) into neurons activated by environmental stimuli.  Neurons expressing the hM3Dq can be stimulated to fire action potentials by administration of a specific chemical ligand.  We found that mice can incorporate anatomically dispersed artificial stimulation of neurons into a discrete memory trace.  These results suggest the ability to incorporate internally generated neural activity into memory representations as a mechanism for linking new learning with previously acquired information.

Show speakers

Is hippocampal LTP really the neural substrate of associative, long-term spatial memory?

Dr David Bannerman, University of Oxford , UK

Abstract

Recent studies with transgenic mice lacking NMDARs in the hippocampus challenge the longstanding hypothesis that hippocampal LTP-like mechanisms underlie the encoding and storage of associative, long-term spatial memories. Hippocampus-specific NMDAR knockout mice (Grin1ΔDGCA1 mice) acquired the standard, fixed location, hidden escape platform version of the watermaze task perfectly well. In a spatial discrimination watermaze task with two visually identical beacons, Grin1ΔDGCA1 mice were again perfectly capable of learning the spatial location of the platform (as measured using probe tests, with the platform and beacons removed from the pool), but were more likely to choose the incorrect, decoy beacon and made more errors overall. This deficit was primarily seen on trials when the mice were started from close to the decoy beacon. Thus, Grin1ΔDGCA1 mice exhibit normal associative spatial memory but are unable to use spatial information to inhibit a conditioned, but inappropriate, behavioural tendency to approach any beacon that looks correct. Extra-hippocampal NMDARs are important for acquiring long-term spatial memories in the watermaze. Thus, it may not be the synaptic plasticity/memory hypothesis that is wrong. Instead, it may be the role of the hippocampus that needs re-examination. Hippocampal NMDARs may perform a critical role for resolving conflict or uncertainty, such as occurs with ambiguous or overlapping memories.

Show speakers

The amygdala versus hippocampus: contrasting patterns of plasticity in health and disease

Professor Sumantra Chattarji, National Centre for Biological Sciences, India

Abstract

The rapid and efficient encoding of fear memories by a brain structure called the amygdala help us cope with threatening stimuli in the future, but also come with a high price tag. These emotional memories etched into the amygdala can become maladaptive. For example, high anxiety and fear are cardinal symptoms of many stress disorders like PTSD. Our study provides insights into the cellular mechanisms underlying these powerful emotional symptoms of stress disorders. We report that chronic stress creates new synaptic contacts that are endowed with more memory-making molecules, which serve as ideal cellular substrates for imprinting powerful emotional memories

Show speakers
Long-term potentiation: enhancing neuroscience for 40 years - satellite meeting Kavli Royal Society Centre, Chicheley Hall Newport Pagnell Buckinghamshire MK16 9JJ