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Long-term potentiation and the modification of synaptic structures in vivo

English title Long-term potentiation and the modification of synaptic structures in vivo
Applicant Holtmaat Anthony
Number 135631
Funding scheme Project funding (Div. I-III)
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.04.2011 - 31.03.2014
Approved amount 250'000.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Cellular Biology, Cytology

Keywords (6)

synaptic plasticity; dendritic spines; barrel cortex; experience-dependent plasticity; 2-photon microscopy; long-term potentiation

Lay Summary (English)

Lead
Lay summary

When an individual undergoes a novel sensory experience the neurons in the brain that handle this information adapt in order to optimize future processing of the same information and to associate it with other inputs. The functional optimization of neuronal processing has previously been measured using electrodes. This has taught us that, after changes in input, the synaptic connections become stronger between some neurons and weaker between others. Another way to express this is 'that some neurons have changed the loudness with which they talk to other neurons'. It was generally believed that the synaptic changes (also called synaptic plasticity) happen in synapses that have long before been established during development of the brain. However, more recently we and others have found that new synapses are continuously formed and lost even in the adult brain, as if neurons are always looking for ways to optimize their connections. The magnitude of these synapse additions and losses is regulated by sensory experience. In the current project we aim to study how sensory input regulates the size and stability of new and old synaptic connections. To do this we use a microscopic technique with which we can peek into the brain of transgenic mice that express a fluorescent marker in particular synapses. This way we can directly monitor the presence and size of synapses. We do this repeatedly over the time course of a month, keeping track of the stable synapses and the ones that appear and disappear. We perform these measurements in a part of the brain that processes information from the whiskers. The sensory input through the whiskers can easily and painlessly be manipulated, so we can compare 'normal' mice with mice that undergo novel sensory experiences or in which we have repeatedly activated neurons. By comparing all these parameters we hope to gain insight in the mechanisms of synaptic plasticity in the intact mouse brain. This is ultimately important for our understanding of learning and memory. New insights from this work will also help to advance the design of new strategies towards memory enhancement and repair in neurological disorders such as Alzheimer's and stroke.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Modality-specific thalamocortical inputs instruct the identity of postsynaptic L4 neurons.
Pouchelon Gabrielle, Gambino Frédéric, Bellone Camilla, Telley Ludovic, Vitali Ilaria, Lüscher Christian, Holtmaat Anthony, Jabaudon Denis (2014), Modality-specific thalamocortical inputs instruct the identity of postsynaptic L4 neurons., in Nature, not known yet(not known ), not known-not known.
Semiautomated correlative 3D electron microscopy of in vivo-imaged axons and dendrites.
Maco Bohumil, Cantoni Marco, Holtmaat Anthony, Kreshuk Anna, Hamprecht Fred A, Knott Graham W (2014), Semiautomated correlative 3D electron microscopy of in vivo-imaged axons and dendrites., in Nature protocols, 9(6), 1354-66.
The Relationship between PSD-95 Clustering and Spine Stability In Vivo
Cane Michele, Maco Bohumil, Knott Graham, Holtmaat Anthony (2014), The Relationship between PSD-95 Clustering and Spine Stability In Vivo, in JOURNAL OF NEUROSCIENCE, 34(6), 2075-2086.
Correlative in vivo 2 photon and focused ion beam scanning electron microscopy of cortical neurons.
Maco B, Holtmaat A, Cantoni M, Kreshuk A, Straehle CN, Hamprecht FA, Knott GW (2013), Correlative in vivo 2 photon and focused ion beam scanning electron microscopy of cortical neurons., in PLoS One, 8(2), e57405.
Optical imaging of structural and functional synaptic plasticity in vivo
Holtmaat Anthony, Randall Jerome, Cane Michele (2013), Optical imaging of structural and functional synaptic plasticity in vivo, in EUROPEAN JOURNAL OF PHARMACOLOGY, 719(1-3), 128-136.
Peripheral deafferentation-driven functional somatosensory map shifts are associated with local, not large-scale dendritic structural plasticity.
Schubert V, Lebrecht D, Holtmaat A (2013), Peripheral deafferentation-driven functional somatosensory map shifts are associated with local, not large-scale dendritic structural plasticity., in J Neurosci, 33(22), 9474-9487.
Imaging Neocortical Neurons through a Chronic Cranial Window.
Holtmaat Anthony, de Paola Vincenzo, Wilbrecht Linda, Trachtenberg Josh T, Svoboda Karel, Portera-Cailliau Carlos (2012), Imaging Neocortical Neurons through a Chronic Cranial Window., in Helmchen and Konnerth (ed.), Cold Spring Harbor press, Cold Spring Harbor, NY, USA, 1-1.
Spike-timing-dependent potentiation of sensory surround in the somatosensory cortex is facilitated by deprivation-mediated disinhibition
Gambino Frédéric, Holtmaat Anthony (2012), Spike-timing-dependent potentiation of sensory surround in the somatosensory cortex is facilitated by deprivation-mediated disinhibition, in Neuron, 75, 490-502.
Synapses let loose for a change: inhibitory synapse pruning throughout experience-dependent cortical plasticity.
Gambino Frédéric, Holtmaat Anthony (2012), Synapses let loose for a change: inhibitory synapse pruning throughout experience-dependent cortical plasticity., in Neuron, 74(2), 214-7.

Collaboration

Group / person Country
Types of collaboration
EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Imaging Synapse Structure and Function in the Vertebrate Brain, Janelia Farm Research Campus Talk given at a conference Sensory-evoked LTP in the mouse barrel cortex 30.03.2014 Ashburn, United States of America Holtmaat Anthony;
Society for Neuroscience annual meeting 2013 Poster Sensory-evoked LTP in the mouse barrel cortex 10.11.2013 San Diego, United States of America Holtmaat Anthony;
4th European Visual Cortex Meeting, St. Cross Castle, Sv. Kriz Zacretje Talk given at a conference Compount mechanism for plasticity in the mouse barrel cortex 14.09.2013 Sv. Kriz Zacretje, Croatia Holtmaat Anthony;
European Synapse Meeting 2013 Talk given at a conference Nonlinear paralemniscal thalamic inputs mediate whisker-evoked heterosynaptic plasticity in the somatosensory cortex 28.08.2013 Bordeaux, France Gambino Frédéric;
IGF Colloquium 2013, 1st colloquium on neural circuits Talk given at a conference Mechanisms of sensory surround potentiation in the mouse barrel cortex 27.06.2013 Montpellier, France Holtmaat Anthony;
Neuronus 2013, IBRO & IRUN Neuroscience forum, Talk given at a conference Compound mechanisms for sensory map plasticity in the mouse barrel cortex 10.05.2013 Cracow, Poland Holtmaat Anthony;
Dominick Purpura Dept Neurosci seminar series at Albert Einstein University Individual talk Compound mechanisms for sensory map plasticity in the mouse barrel cortex 04.04.2013 Bronx, NY, United States of America Holtmaat Anthony;
Neuroscience seminar series CSHL Individual talk Compound mechanisms for sensory map plasticity in the mouse barrel cortex 01.04.2013 Cold Spring Harbor, United States of America Holtmaat Anthony;
FENS meeting 2012 Talk given at a conference Compound mechanisms for sensory map plasticity in the mouse barrel cortex 14.07.2012 Barcelona, Spain Holtmaat Anthony;
Satelite event FENS forum 2012, synaptic basis of disease Poster A compound mechanism of deprivation-mediated sensory surround potentiation in the adult somatosensory cortex 09.07.2012 Geneva, Switzerland Gambino Frédéric;
Imaging neuronal functions: from molecules to circuits, Jacques Monod Conference, Roscoff 2012 Poster Mapping of Large-scale and Long-term Functional and Structural Plasticity in Mouse Somatosensory Cortex 30.06.2012 Roscov, France Lebrecht Daniel;
ONWAR-Erasmus Imaging Course Individual talk Imaging of experience-dependent plasticity in the mouse somatosensory cortex in vivo 20.04.2012 Rotterdam, Netherlands Holtmaat Anthony;
Workshop on Biology and Pathology of Synaptic and Neuronal Plasticity Individual talk Experience dependent plasticity in the mouse somatosensory cortex 02.03.2012 Turin, Italy Holtmaat Anthony;
Society for Neuroscience annual meeting 2011 Talk given at a conference Short and long term plasticity in the mouse barrel cortex 15.11.2011 Washington DC, United States of America Holtmaat Anthony;
Society for Neuroscience annual meeting 2011 Poster A compound mechanism for correlation-based plasticity in the mouse barrel cortex in vivo 13.11.2011 Washington DC, United States of America Holtmaat Anthony; Gambino Frédéric;
SiNAPSA Neuroscience Conference 2011 Talk given at a conference Short and long term structural plasticity in the mouse neocortex 22.09.2011 Ljubjana, Slovenia Holtmaat Anthony;


Associated projects

Number Title Start Funding scheme
139229 Platform for integrated mouse behavior (PIMB) 01.12.2011 R'EQUIP
153448 Activity-dependent functional and structural plasticity in the somatosensory cortex in vivo 01.04.2014 Project funding (Div. I-III)
154453 Function and structure of neuromodulatory inputs to the cerebral cortex 01.01.2015 Sinergia
120685 Experience-dependent structural plasticity of synapses in vivo 01.04.2008 Project funding (Div. I-III)
127289 Structure, Function and Plasticity of the Barrel Cortex 01.01.2010 Sinergia

Abstract

Novel sensory experience leads to changes in the functional properties of the adult neocortex. Experience-dependent cortical plasticity is thought to be an important aspect of perceptual learning, and likely depends on activity-dependent strengthening and weakening of pre-established synapses as well as on structural plasticity, including synapse formation and elimination. There is a paucity of information on how structural plasticity relates to functional plasticity in vivo. In vitro studies have shown that synaptic structures such as spines undergo rapid modifications upon strong synaptic stimulation, inhibition or LTP and LTD-like processes. However, in vivo studies so far have mostly focused on spine formation and elimination in relation to long-term sensory map plasticity and motor learning. Detailed information on the structural changes of pre-established synapses in vivo, that putatively relate to early phases of neuronal plasticity is currently lacking. We hypothesize that immediate forms of plasticity in vivo include structural changes of pre-established synaptic connections, analogous to the observations in LTP and LTD paradigms in brain slices. In this research proposal we will use an experimental strategy that combines two-photon laser scanning microscopy (2PLSM) with whole-cell electrophysiological recordings in vivo to study spine structural changes during whisker stimulation induced LTP and LTD. We will also perform a detailed analysis of subcellular structural changes in experience-dependent plasticity paradigms in vivo by measuring sizes and the relocation of dendritic organelles such as the PSD, cytoskeleton, ER and mitochondira. Furthermore, in collaboration with G. Knott at the EPFL in Lausanne we will develop and employ a novel method for high throughput correlative reconstruction of the in vivo-imaged dendrites’ ultrastructure, based on focused ion beam milling combined with serial section scanning EM. Improving our knowledge of how neurons in the cortex modulate the structure of their synaptic connections in response to changes in input and experience is key to understanding how we store information and acquire new skills. In addition, it will help to advance the design of new strategies towards memory enhancement and neuronal repair in neurodegenerative diseases and after traumatic injury.
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