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1. Lights on Endocannabinoid-Mediated Synaptic Potentiation

Author

Charlotte Piette, Yihui Cui, Nicolas Gervasi, and Laurent Venance

Subjects
endocannabinoids, synaptic plasticity, long-term potentiation, neuromodulation, GABAergic interneurons, cannabinoid receptor type-1, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

The endocannabinoid (eCB) system is a lipid-based neurotransmitter complex that plays crucial roles in the neural control of learning and memory. The current model of eCB-mediated retrograde signaling is that eCBs released from postsynaptic elements travel retrogradely to presynaptic axon terminals, where they activate cannabinoid type-1 receptors (CB1Rs) and ultimately decrease neurotransmitter release on a short- or long-term scale. An increasing body of evidence has enlarged this view and shows that eCBs, besides depressing synaptic transmission, are also able to increase neurotransmitter release at multiple synapses of the brain. This indicates that eCBs act as bidirectional regulators of synaptic transmission and plasticity. Recently, studies unveiled links between the expression of eCB-mediated long-term potentiation (eCB-LTP) and learning, and between its dysregulation and several pathologies. In this review article, we first distinguish the various forms of eCB-LTP based on their mechanisms, resulting from homosynaptically or heterosynaptically-mediated processes. Next, we consider the neuromodulation of eCB-LTP, its behavioral impact on learning and memory, and finally, eCB-LTP disruptions in various pathologies and its potential as a therapeutic target in disorders such as stress coping, addiction, Alzheimer’s and Parkinson’s disease, and pain. Cannabis is gaining popularity as a recreational substance as well as a medicine, and multiple eCB-based drugs are under development. In this context, it is critical to understand eCB-mediated signaling in its multi-faceted complexity. Indeed, the bidirectional nature of eCB-based neuromodulation may offer an important key to interpret the functions of the eCB system and how it is impacted by cannabis and other drugs.

Published
2020
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2. Lights on Endocannabinoid-Mediated Synaptic Potentiation

Author

Yihui Cui, Nicolas Gervasi, Charlotte Piette, and Laurent Venance

Subjects
0301 basic medicine, Mini Review, Context (language use), Biology, Neurotransmission, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, excitation-inhibition balance, endocannabinoids, Neurotransmitter, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Molecular Biology, long-term potentiation, synaptic plasticity, Long-term potentiation, Endocannabinoid system, Neuromodulation (medicine), GABAergic interneurons, 030104 developmental biology, chemistry, neuromodulation, Synaptic plasticity, Retrograde signaling, cannabinoid receptor type-1, learning and memory, Neuroscience, 030217 neurology & neurosurgery
Abstract

The endocannabinoid (eCB) system is a lipid-based neurotransmitter complex that plays crucial roles in the neural control of learning and memory. The current model of eCB-mediated retrograde signaling is that eCBs released from postsynaptic elements travel retrogradely to presynaptic axon terminals, where they activate cannabinoid type-1 receptors (CB1Rs) and ultimately decrease neurotransmitter release on a short- or long-term scale. An increasing body of evidence has enlarged this view and shows that eCBs, besides depressing synaptic transmission, are also able to increase neurotransmitter release at multiple synapses of the brain. This indicates that eCBs act as bidirectional regulators of synaptic transmission and plasticity. Recently, studies unveiled links between the expression of eCB-mediated long-term potentiation (eCB-LTP) and learning, and between its dysregulation and several pathologies. In this review article, we first distinguish the various forms of eCB-LTP based on their mechanisms, resulting from homosynaptically or heterosynaptically-mediated processes. Next, we consider the neuromodulation of eCB-LTP, its behavioral impact on learning and memory, and finally, eCB-LTP disruptions in various pathologies and its potential as a therapeutic target in disorders such as stress coping, addiction, Alzheimer’s and Parkinson’s disease, and pain. Cannabis is gaining popularity as a recreational substance as well as a medicine, and multiple eCB-based drugs are under development. In this context, it is critical to understand eCB-mediated signaling in its multi-faceted complexity. Indeed, the bidirectional nature of eCB-based neuromodulation may offer an important key to interpret the functions of the eCB system and how it is impacted by cannabis and other drugs.

Published
2020

3. Dopamine-endocannabinoid interactions mediate spike-timing dependent potentiation in the striatum

Author

Yihui Cui, Bérangère Detraux, Sylvie Perez, Laurent Venance, Alban de Kerchove d'Exaerde, Bertrand Degos, Amandine Cornil, Hao Xu, Hugues Berry, Ilya Prokin, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratory of Neurophysiology [Brussels], Université libre de Bruxelles (ULB), Artificial Evolution and Computational Biology (BEAGLE), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria), Walloon Excellence in Life sciences and BIOtechnology [Liège] (WELBIO), This work was supported by grants from INSERM, Collège de France, the Agence Nationale pour la Recherche (ANR-CRCNS Dopaciumcity), France Parkinson, INRIA, CNRS, Fondation deFrance, FRS-FNRS and the Ecole des Neurosciences de Paris. BD and AC are research Fellow of the FRS-FNRS (Belgium). AKE is a Senior Research Associate of the FRS-FNRS and a WELBIO investigator and is supported by FRS-FNRS (Belgium), FER from ULB, Action de Recherche Concertée form the CFWB., ANR-14-NEUC-0003,DOPACIUMCITY,Dopamine modulation of calcium influx underlying synaptic plasticity(2014), Collège de France (CdF (institution))-Université Paris sciences et lettres (2020-....) (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Dynamics and Pathophysiology of neuronal networks, Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies du Système Nerveux [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Inria Grenoble - Rhône-Alpes, Université de Lyon-Université Lumière - Lyon 2 (UL2), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (2020-....) (PSL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Inria Grenoble - Rhône-Alpes, Berry, Hugues, and Recherche collaborative en neurosciences computationnelles - Dopamine modulation of calcium influx underlying synaptic plasticity - - DOPACIUMCITY2014 - ANR-14-NEUC-0003 - CRCNS - VALID

Subjects
0301 basic medicine, Dopamine, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Long-Term Potentiation, Action Potentials, General Physics and Astronomy, Striatum, Procedural memory, Antiparkinson Agents, Levodopa, Rats, Sprague-Dawley, 0302 clinical medicine, Basal ganglia, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Neurophysiologie, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Multidisciplinary, musculoskeletal, neural, and ocular physiology, Dopaminergic, Parkinson Disease, Long-term potentiation, Endocannabinoid system, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.drug, Science, Mice, Transgenic, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Receptors, Dopamine D2, Long-Term Synaptic Depression, General Chemistry, Mice, Inbred C57BL, Neostriatum, Disease Models, Animal, 030104 developmental biology, nervous system, Synaptic plasticity, lcsh:Q, Neuroscience, 030217 neurology & neurosurgery, Endocannabinoids
Abstract

Dopamine modulates striatal synaptic plasticity, a key substrate for action selection and procedural learning. Thus, characterizing the repertoire of activity-dependent plasticity in striatum and its dependence on dopamine is of crucial importance. We recently unraveled a striatal spike-timing-dependent long-term potentiation (tLTP) mediated by endocannabinoids (eCBs) and induced with few spikes (~5–15). Whether this eCB-tLTP interacts with the dopaminergic system remains to be investigated. Here, we report that eCB-tLTP is impaired in a rodent model of Parkinson’s disease and rescued by L-DOPA. Dopamine controls eCB-tLTP via dopamine type-2 receptors (D2R) located presynaptically in cortical terminals. Dopamine–endocannabinoid interactions via D2R are required for the emergence of tLTP in response to few coincident pre- and post-synaptic spikes and control eCB-plasticity by modulating the long-term potentiation (LTP)/depression (LTD) thresholds. While usually considered as a depressing synaptic function, our results show that eCBs in the presence of dopamine constitute a versatile system underlying bidirectional plasticity implicated in basal ganglia pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018

4. Endocannabinoid-LTP Mediated by CB1 and TRPV1 Receptors Encodes for Limited Occurrences of Coincident Activity in Neocortex

Author

Sylvie Perez, Laurent Venance, Yihui Cui, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biology, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, neocortex, medicine, CB1R, endocannabinoids, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Original Research, Neocortex, Spike-timing-dependent plasticity, musculoskeletal, neural, and ocular physiology, Long-term potentiation, spike-timing dependent plasticity, Endocannabinoid system, TRPV1, Hebbian plasticity, 030104 developmental biology, Hebbian theory, medicine.anatomical_structure, Metabotropic glutamate receptor, CB 1 R, Synaptic plasticity, NMDA receptor, LTP, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Synaptic efficacy changes, long-term potentiation (LTP) and depression (LTD), underlie various forms of learning and memory. Synaptic plasticity is generally assessed under prolonged activation, whereas learning can emerge from few or even a single trial. Here, we investigated the existence of rapid responsiveness of synaptic plasticity in response to a few number of spikes, in neocortex in a synaptic Hebbian learning rule, the spike-timing-dependent plasticity (STDP). We investigated the effect of lowering the number of pairings from 100 to 50, and 10 on STDP expression, using whole-cell recordings from pyramidal cells in rodent somatosensory cortical brain slices. We found that a low number of paired stimulations induces LTP at neocortical layer 4-2/3 synapses. Besides the asymmetric Hebbian STDP reported in the neocortex induced by 100 pairings, we observed a symmetric anti-Hebbian LTD for 50 pairings and unveiled a unidirectional Hebbian spike-timing-dependent LTP (tLTP) induced by 10-15 pairings. This tLTP was not mediated by NMDA receptor activation but requires CB 1 receptors and transient receptor potential vanilloid type-1 (TRPV1) activated by endocannabinoids (eCBs). eCBs have been widely described as mediating short-and long-term synaptic depression. Here, the eCB-tLTP reported at neocortical synapses could constitute a substrate operating in the online learning of new associative memories or during the initial stages of learning. In addition, these findings should provide useful insight into the mechanisms underlying eCB-plasticity occurring during marijuana intoxication.

Published
2018

5. Robustness of STDP to spike timing jitter

Author

Hugues Berry, Alexandre Mendes, Laurent Venance, Yihui Cui, Ilya Prokin, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Artificial Evolution and Computational Biology (BEAGLE), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université Lumière - Lyon 2 (UL2), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria), ANR-14-NEUC-0003,DOPACIUMCITY,Dopamine modulation of calcium influx underlying synaptic plasticity(2014), Centre interdisciplinaire de recherche en biologie ( CIRB ), Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Artificial Evolution and Computational Biology ( BEAGLE ), Laboratoire d'InfoRmatique en Image et Systèmes d'information ( LIRIS ), Université Lumière - Lyon 2 ( UL2 ) -École Centrale de Lyon ( ECL ), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Université Lumière - Lyon 2 ( UL2 ) -École Centrale de Lyon ( ECL ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Cardiovasculaire, métabolisme, diabétologie et nutrition ( CarMeN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Dynamics and Pathophysiology of neuronal networks, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Inria Grenoble - Rhône-Alpes, Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL), Berry, Hugues, and Recherche collaborative en neurosciences computationnelles - Dopamine modulation of calcium influx underlying synaptic plasticity - - DOPACIUMCITY2014 - ANR-14-NEUC-0003 - CRCNS - VALID

Subjects
0301 basic medicine, Computer science, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Long-Term Potentiation, Models, Neurological, lcsh:Medicine, Article, Spike-timing-dependent plasticity, Synapse, 03 medical and health sciences, Neural activity, 0302 clinical medicine, Robustness (computer science), Postsynaptic potential, Biological neural network, lcsh:Science, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Jitter, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Multidisciplinary, Neuronal Plasticity, musculoskeletal, neural, and ocular physiology, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, lcsh:R, Neurophysiology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Electrophysiology, 030104 developmental biology, Hebbian theory, nervous system, Synapses, [ SCCO.NEUR ] Cognitive science/Neuroscience, Spike (software development), lcsh:Q, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery, Biophysical models
Abstract

In Hebbian plasticity, neural circuits adjust their synaptic weights depending on patterned firing of action potential on either side of the synapse. Spike-timing-dependent plasticity (STDP) is an experimental implementation of Hebb’s postulate that relies on the precise order and the millisecond timing of the paired activities in pre- and postsynaptic neurons. In recent years, STDP has attracted considerable attention in computational and experimental neurosciences. However, canonical STDP is assessed with deterministic (constant) spike timings and time intervals between successive pairings, thus exhibiting a regularity that strongly differs from the biological variability. Hence, the emergence of STDP from noisy neural activity patterns as expected in in vivo-like firing remains unresolved. Here, we used noisy STDP stimulations where the spike timing and/or the interval between successive pairings were jittered. We explored with a combination of experimental neurophysiology and mathematical modeling, the impact of jittering on three distinct forms of STDP at corticostriatal synapses: NMDAR-mediated tLTP, endocannabinoid-mediated tLTD and endocannabinoid-mediated tLTP. As the main result, we found a differential sensitivity to jittered spike timing: NMDAR-tLTP was highly fragile whereas endocannabinoid-plasticity (tLTD and tLTP) appeared more resistant. Moreover, when the frequency or the number of pairings was increased, NMDAR-tLTP became more robust and could be expressed despite strong jittering of the spike timing. Taken together, our results identify endocannabinoid-mediated plasticity as a robust form of STDP while the sensitivity to jitter of NMDAR-tLTP varies with activity frequency. This provides new insights into the mechanisms at play during the different phases of learning and memory and the emergence of Hebbian plasticity in in vivo-like firing.

Published
2018

6. Endocannabinoid dynamics gate spike-timing dependent depression and potentiation

Author

Yihui Cui, Ilya Prokin, Stéphane Genet, Hao Xu, Bruno Delord, Hugues Berry, Laurent Venance, Dynamics and Pathophysiology of neuronal networks, Institut National de la Santé et de la Recherche Médicale (INSERM), Artificial Evolution and Computational Biology (BEAGLE), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (2020-....) (PSL), Institut des Systèmes Intelligents et Robotique (ISIR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Action-Neuroimagerie-Modelisation (ANIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2), Institut des Systèmes Intelligents et de Robotique (ISIR), AMAC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), ANR-14-NEUC-0003,DOPACIUMCITY,Dopamine modulation of calcium influx underlying synaptic plasticity(2014), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Collège de France (CdF (institution))-Université Paris sciences et lettres (2020-....) (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Berry, Hugues, and Recherche collaborative en neurosciences computationnelles - Dopamine modulation of calcium influx underlying synaptic plasticity - - DOPACIUMCITY2014 - ANR-14-NEUC-0003 - CRCNS - VALID

Subjects
0301 basic medicine, CB1 receptor, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Action Potentials, corticostriatal synapse, Rats, Sprague-Dawley, Synapse, 0302 clinical medicine, Biology (General), ComputingMilieux_MISCELLANEOUS, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Neuronal Plasticity, Spike-timing-dependent plasticity, Calcineurin, General Neuroscience, Glutamate receptor, Long-term potentiation, General Medicine, Endocannabinoid system, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], basal ganglia, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, QH301-705.5, Science, Biology, Neurotransmission, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Animals, [INFO]Computer Science [cs], endocannabinoids, Cannabinoid Receptor Antagonists, Cannabinoid Receptor Agonists, synaptic plasticity, General Immunology and Microbiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Somatosensory Cortex, spike-timing dependent plasticity, Models, Theoretical, Cyclic AMP-Dependent Protein Kinases, Electrophysiology, 030104 developmental biology, Ventral Striatum, Synaptic plasticity, Rat, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], signalling pathways, Neuroscience, 030217 neurology & neurosurgery
Abstract

Synaptic plasticity is a cardinal cellular mechanism for learning and memory. The endocannabinoid (eCB) system has emerged as a pivotal pathway for synaptic plasticity because of its widely characterized ability to depress synaptic transmission on short- and long-term scales. Recent reports indicate that eCBs also mediate potentiation of the synapse. However, it is not known how eCB signaling may support bidirectionality. Here, we combined electrophysiology experiments with mathematical modeling to question the mechanisms of eCB bidirectionality in spike-timing dependent plasticity (STDP) at corticostriatal synapses. We demonstrate that STDP outcome is controlled by eCB levels and dynamics: prolonged and moderate levels of eCB lead to eCB-mediated long-term depression (eCB-tLTD) while short and large eCB transients produce eCB-mediated long-term potentiation (eCB-tLTP). Moreover, we show that eCB-tLTD requires active calcineurin whereas eCB-tLTP necessitates the activity of presynaptic PKA. Therefore, just like glutamate or GABA, eCB form a bidirectional system to encode learning and memory. DOI: http://dx.doi.org/10.7554/eLife.13185.001, eLife digest Learning and memory depend on processes that alter the connections – or synapses – between neurons in the brain. For example, molecules called endocannabinoids can alter synapses to decrease the influence that one neuron has on another neuron’s activity. This “synaptic depression” is an important mechanism through which the brain can adapt to an experience. However, recent research also suggests that endocannabinoids might also increase the influence one neuron has on another neuron’s activity by strengthening the synaptic connection between neurons. This opposite process is known as synaptic potentiation, and is also important for learning from experience. But how do endocannabinoids manage to produce opposing effects? Using a combination of electrophysiological recording experiments and mathematical modeling, Cui et al. have now deciphered the molecular mechanisms that govern the action of endocannabinoids at key synapses in rat brain slices. This revealed that both the levels and timing of endocannabinoid release control changes in the strength of the synaptic connections. Electrical stimulations that produced moderate amounts of endocannabinoids over a prolonged period led to synaptic depression. However, stimulation that produced short but large endocannabinoid peaks caused synaptic potentiation. The enzymes that control endocannabinoid levels thus play a crucial role in determining whether a given stimulation leads to the strengthening or weakening of a synaptic connection. In the type of synapses studied by Cui et al., changes to synaptic strength also depend on another chemical called dopamine. Abnormal dopamine production is implicated in a number of disorders, including Parkinson’s disease and addiction. Future work will therefore investigate how dopamine controls endocannabinoid-dependent changes to the strength of synapses. DOI: http://dx.doi.org/10.7554/eLife.13185.002

Published
2016

8. Distinct coincidence detectors govern the corticostriatal spike timing-dependent plasticity

Author

Laurent Venance, Jean-Michel Deniau, Vincent Paillé, Teresa Morera-Herreras, Yihui Cui, and Elodie Fino

Subjects
0303 health sciences, Physiology, Spike-timing-dependent plasticity, Long-term potentiation, Biology, gamma-Aminobutyric acid, 03 medical and health sciences, 0302 clinical medicine, Metabotropic glutamate receptor, Neuroplasticity, Excitatory postsynaptic potential, medicine, NMDA receptor, Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology, Coincidence detection in neurobiology, medicine.drug
Abstract

Corticostriatal projections constitute the main input to the basal ganglia, an ensemble of interconnected subcortical nuclei involved in procedural learning. Thus, long-term plasticity at corticostriatal synapses would provide a basic mechanism for the function of basal ganglia in learning and memory. We had previously reported the existence of a corticostriatal anti-Hebbian spike timing-dependent plasticity (STDP) at synapses onto striatal output neurons, the medium-sized spiny neurons. Here, we show that the blockade of GABAergic transmission reversed the time dependence of corticostriatal STDP. We explored the receptors and signalling mechanisms involved in the corticostriatal STDP. Although classical models for STDP propose NMDA receptors as the unique coincidence detector, the involvement of multiple coincidence detectors has also been demonstrated. Here, we show that corticostriatal STDP depends on distinct coincidence detectors. Specifically, long-term potentiation is dependent on NMDA receptor activation, while long-term depression requires distinct coincidence detectors: the phospholipase Cβ (PLCβ) and the inositol-trisphosphate receptor (IP3R)-gated calcium stores. Furthermore, we found that PLCβ activation is controlled by group-I metabotropic glutamate receptors, type-1 muscarinic receptors and voltage-sensitive calcium channel activities. Activation of PLCβ and IP3Rs leads to robust retrograde endocannabinoid signalling mediated by 2-arachidonoyl-glycerol and cannabinoid CB1 receptors. Interestingly, the same coincidence detectors govern the corticostriatal anti-Hebbian STDP and the Hebbian STDP reported at cortical synapses. Therefore, LTP and LTD induced by STDP at corticostriatal synapses are mediated by independent signalling mechanisms, each one being controlled by distinct coincidence detectors.

Published
2010

9. Endocannabinoids mediate spike-timing dependent potentiation and depression: a model-based experimental approach

Author

Laurent Venance, Hugues Berry, Bruno Delord, Stéphane Genet, Elodie Fino, Vincent Paillé, Yihui Cui, Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Systèmes Intelligents et de Robotique (ISIR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), AMAC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria), Artificial Evolution and Computational Biology (BEAGLE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Cymbalyuk, Gennady S. and Prinz, Astrid A., Team Dynamic and Pathophysiology of Neuronal Networks, Center for Interdisciplinary Research in Biology (CIRB), École normale supérieure - Paris (ENS-PSL), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution)), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Inria Grenoble - Rhône-Alpes, BMC, Ed., Cymbalyuk, Gennady S. and Prinz, Astrid A., Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Venance, Laurent

Subjects
0303 health sciences, Voltage-dependent calcium channel, Post-tetanic potentiation, Spike-timing-dependent plasticity, musculoskeletal, neural, and ocular physiology, General Neuroscience, Neurosciences, Long-term potentiation, Context (language use), Biology, Endocannabinoid system, 03 medical and health sciences, Cellular and Molecular Neuroscience, Transient receptor potential channel, 0302 clinical medicine, nervous system, Postsynaptic potential, Neurons and Cognition, Oral Presentation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Activity-dependent long-term potentiation (LTP) and depression (LTD) of synaptic strength underlie multiple forms of learning and memory. Endocannabinoids (eCBs) have consistently been described as mediators of short- or long-term synaptic depression through the activation of the endocannabinoid-type-1 receptor (CB1R) or the transient receptor potential vanilloid-type-1 (TRPV1). Here we investigated whether eCBs could also promote long-term potentiation, an essential requirement for eCBs to be a genuine bidirectional system and to fully encode for learning and memory. To this aim, we combined in vitro spike timing-dependent plasticity (STDP) protocols in rodents and a biophysical model of the signaling pathways likely to be involved. The model describes the temporal dynamics of three main signaling systems: the postsynaptic NMDAR-CaMKII pathway (adapted from [1]), the postsynaptic mGluR-PLCβ system (adapted from [2]) as well as postsynaptic eCB synthesis and subsequent activation of postsynaptic TRPV1 and presynaptic CB1R in a retrograde fashion. Using the model to drive the experiments, we uncovered the existence of an eCB-mediated spike-timing dependent potentiation (eCB-LTP). This eCB-LTP is homosynaptic, astrocyte-independent and expressed in young and adult animals and across various brain regions (cortex and striatum), supporting its role as a widespread signaling system for spike-based plasticity. We deciphered the signaling pathways (pre- and postsynaptic receptors and enzymes) involved in this new form of plasticity and demonstrated that eCB plasticity has a postynaptic induction and a presynaptic maintenance. On the postsynaptic side, our results show that the dynamics of free cytosolic calcium is a key element for eCB-LTP induction. eCB-LTP is triggered when eCB transients reach sufficiently high levels. Since the enzymes that synthetize eCBs are calcium-activated, eCB-LTP induction requires large levels of cytosolic calcium. On the presynaptic side, eCBs encode for bidirectional plasticity via a triad composed of eCB levels, presynaptic PKA and presynaptic CaN: intermediate eCB levels promote presynaptic CaN activity, that yields eCB-LTD, whereas large eCB amplitudes favor presynaptic PKA activity, which leads to eCB-LTP. Both effects are predicted to rely on the inhibition exerted by activated CB1R on presynaptic adenylate cyclase and P/Q-type voltage-gated calcium channels. Moreover, we show that eCB-LTP and eCB-LTD can be induced sequentially in the same neuron, depending on the cellular conditioning paradigm. Therefore, our results demonstrate that eCBs, just like glutamatergic or GABAergic signaling, form a generic system able to encode for bidirectional plasticity and capable of genuine homeostasis. Lastly, we found that eCB-LTP is triggered by very few paired spikes (5 to 10 post-pre spikes at 1 Hz are enough). Thus, eCB-LTP provides synapses with a mechanism able to react to the very first occurrences of incoming activity. This ability strongly contrasts with NMDAR-dependent LTP which, in a classical (1 Hz) STDP context, requires the iteration of at least 75-100 paired stimulations to be expressed, at odds with the observations that new associative memories and behavioral rules can be learned within few or even a single trials in mammals (e.g. [3]). Our results suggest that eCB-LTP may represent a neuronal substrate for such rapid learning abilities.

Published
2013

10. The Effects of NMDA Subunit Composition on Calcium Influx and Spike Timing-Dependent Plasticity in Striatal Medium Spiny Neurons

Author

Rebekah C. Evans, Kai Du, Jeanette Hellgren Kotaleski, Kim T. Blackwell, Laurent Venance, Tom Sheehan, Teresa Morera-Herreras, Yihui Cui, Krasnow Institute for Advanced Study [Fairfax], George Mason University [Fairfax], Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroscience Department, Karolinska Institutet [Stockholm], This work was supported by NINDS through the pre-doctoral NRSA grant 1F31NS066645 awarded to Rebekah Evans, the Joint NIH-NSF CRCNS program through grant R01 AA016022, and the ONR grant MURI N00014-10-1-0198., Autard, Delphine, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Action Potentials, Ion Channels, 0302 clinical medicine, Learning and Memory, Current clamp, lcsh:QH301-705.5, Neurons, 0303 health sciences, Neuronal Plasticity, Ecology, Spike-timing-dependent plasticity, Long-term potentiation, Depolarization, Anatomy, Single Neuron Function, Computational Theory and Mathematics, Modeling and Simulation, NMDA receptor, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, N-Methylaspartate, Models, Neurological, chemistry.chemical_element, Neurophysiology, Biology, Calcium, Medium spiny neuron, 03 medical and health sciences, Cellular and Molecular Neuroscience, Structure-Activity Relationship, Developmental Neuroscience, Genetics, Animals, Humans, Computer Simulation, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Computational Neuroscience, Corpus Striatum, Protein Subunits, lcsh:Biology (General), chemistry, nervous system, Models, Chemical, Cellular Neuroscience, Synaptic plasticity, Synapses, Neuroscience, 030217 neurology & neurosurgery, Synaptic Plasticity
Abstract

Calcium through NMDA receptors (NMDARs) is necessary for the long-term potentiation (LTP) of synaptic strength; however, NMDARs differ in several properties that can influence the amount of calcium influx into the spine. These properties, such as sensitivity to magnesium block and conductance decay kinetics, change the receptor's response to spike timing dependent plasticity (STDP) protocols, and thereby shape synaptic integration and information processing. This study investigates the role of GluN2 subunit differences on spine calcium concentration during several STDP protocols in a model of a striatal medium spiny projection neuron (MSPN). The multi-compartment, multi-channel model exhibits firing frequency, spike width, and latency to first spike similar to current clamp data from mouse dorsal striatum MSPN. We find that NMDAR-mediated calcium is dependent on GluN2 subunit type, action potential timing, duration of somatic depolarization, and number of action potentials. Furthermore, the model demonstrates that in MSPNs, GluN2A and GluN2B control which STDP intervals allow for substantial calcium elevation in spines. The model predicts that blocking GluN2B subunits would modulate the range of intervals that cause long term potentiation. We confirmed this prediction experimentally, demonstrating that blocking GluN2B in the striatum, narrows the range of STDP intervals that cause long term potentiation. This ability of the GluN2 subunit to modulate the shape of the STDP curve could underlie the role that GluN2 subunits play in learning and development., Author Summary The striatum of the basal ganglia plays a key role in fluent motor control; pathology in this structure causes the motor symptoms of Parkinson's Disease and Huntington's Chorea. A putative cellular mechanism underlying learning of motor control is synaptic plasticity, which is an activity dependent change in synaptic strength. A known mediator of synaptic potentiation is calcium influx through the NMDA-type glutamate receptor. The NMDA receptor is sensitive to the timing of neuronal activity, allowing calcium influx only when glutamate release and a post-synaptic depolarization coincide temporally. The NMDA receptor is comprised of specific subunits that modify its sensitivity to neuronal activity and these subunits are altered in animal models of Parkinson's disease. Here we use a multi-compartmental model of a striatal neuron to investigate the effect of different NMDA subunits on calcium influx through the NMDA receptor. Simulations show that the subunit composition changes the temporal intervals that allow coincidence detection and strong calcium influx. Our experiments manipulating the dominate subunit in brain slices show that the subunit effect on calcium influx predicted by our computational model is mirrored by a change in the amount of potentiation that occurs in our experimental preparation.

Published
2012

11. Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction of long-term potentiation in rats

Author

Xiaohua Cao, Yu-Qiu Zhang, Yihui Cui, Hong Cao, and Zhi-Qi Zhao

Subjects
MAPK/ERK pathway, medicine.medical_specialty, Time Factors, Physiology, Long-Term Potentiation, In Vitro Techniques, CREB, Gyrus Cinguli, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Internal medicine, medicine, LTP induction, Animals, Enzyme Inhibitors, Phosphorylation, Cyclic AMP Response Element-Binding Protein, Extracellular Signal-Regulated MAP Kinases, Flavonoids, biology, Chemistry, musculoskeletal, neural, and ocular physiology, General Neuroscience, MEK inhibitor, Excitatory Postsynaptic Potentials, Long-term potentiation, General Medicine, Immunohistochemistry, Electric Stimulation, Rats, Up-Regulation, Endocrinology, nervous system, Excitatory postsynaptic potential, biology.protein, NMDA receptor, Original Article, Tetanic stimulation, Microelectrodes
Abstract

To explore the role of the extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) pathway in the induction of long-term potentiation (LTP) in the anterior cingulate cortex (ACC) that may be implicated in pain-related negative emotion.LTP of field potential was recorded in ACC slice and the expressions of phospho-ERK (pERK) and phospho-CREB (pCREB) were examined using immunohistochemistry method.LTP could be induced stably in ACC slice by high frequency stimulation (2-train, 100 Hz, 1 s), while APv (an antagonist of NMDA receptor) could block the induction of LTP in the ACC, indicating that LTP in this experiment was NMDA receptor-dependent. Bath application of PD98059 (50 micromol/L), a selective MEK inhibitor, at 30 min before tetanic stimulation could completely block the induction of LTP. Moreover, the protein level of pERK in the ACC was transiently increased after LTP induction, starting at 5 min and returning to basal at 1 h after tetanic stimulation. The protein level of pCREB was also increased after LTP induction. The up-regulation in pERK and pCREB expressions could be blocked by pretreatment of PD98059. Double immunostaining showed that after LTP induction, most pERK was co-localized with pCREB.NMDA receptor and ERK-CREB pathway are necessary for the induction of LTP in rat ACC and may play important roles in pain emotion.

Published
2009

12. A novel derivative of xanomeline improved memory function in aged mice

Author

Wen Si, Jing Jin, Shi-Ning Deng, Liang Yin, Xiaohua Cao, Shu-Ming An, and Yihui Cui

Subjects
Agonist, Aging, Physiology, medicine.drug_class, Pyridines, Long-Term Potentiation, Hippocampus, Pharmacology, Muscarinic Agonists, Oxalate, Lethal Dose 50, chemistry.chemical_compound, Mice, Memory, Thiadiazoles, medicine, Animals, Dose-Response Relationship, Drug, General Neuroscience, Brain, Excitatory Postsynaptic Potentials, Long-term potentiation, General Medicine, Acute toxicity, chemistry, Synaptic plasticity, Excitatory postsynaptic potential, Original Article, Xanomeline, Neuroscience
Abstract

To characterize the function of a new xanomeline-derived M1 agonist, 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6- tetrahydro-1-methylpyridine Oxalate (EUK1001), the acute toxicity and the effects on synaptic plasticity and cognition of EUK1001 were evaluated.To examine the median lethal dose (LD50) of EUK1001, a wide dose range of EUK1001 was administered by p.o. and i.p. in aged mice. Furthermore, novel object recognition task and in vitro electrophysiological technique were utilized to investigate the effects of EUK1001 on recognition memory and hippocampal synaptic plasticity in aged mice.EUK1001 exhibited lower toxicity than xanomeline, and improved the performance of aged mice in the novel object recognition test. In addition, bath application of 1 micromol/L EUK1001 directly induced long-term potentiation in the hippocampus slices.We conclude that EUK1001 can improve the age-related cognitive deficits.

Published
2008

13. Forebrain NR2B Overexpression Facilitating the Prefrontal Cortex Long-Term Potentiation and Enhancing Working Memory Function in Mice

Author

Joe Z. Tsien, Liguo Yang, Jing Jin, Xuliang Zhang, Yihui Cui, Dan Du, Qingwen Zeng, Huiting Yu, Xiaohua Cao, and Hao Xu

Subjects
Long-Term Potentiation, lcsh:Medicine, Prefrontal Cortex, Hippocampus, Mice, Transgenic, Water maze, Biology, Receptors, N-Methyl-D-Aspartate, Mice, Behavioral Neuroscience, Prosencephalon, Learning and Memory, Animals, lcsh:Science, Prefrontal cortex, Multidisciplinary, Working memory, musculoskeletal, neural, and ocular physiology, lcsh:R, Long-term potentiation, Animal Cognition, Electrophysiology, Memory, Short-Term, nervous system, Forebrain, Synaptic plasticity, NMDA receptor, lcsh:Q, Neuroscience, psychological phenomena and processes, Research Article
Abstract

Prefrontal cortex plays an important role in working memory, attention regulation and behavioral inhibition. Its functions are associated with NMDA receptors. However, there is little information regarding the roles of NMDA receptor NR2B subunit in prefrontal cortical synaptic plasticity and prefrontal cortex-related working memory. Whether the up-regulation of NR2B subunit influences prefrontal cortical synaptic plasticity and working memory is not yet clear. In the present study, we measured prefrontal cortical synaptic plasticity and working memory function in NR2B overexpressing transgenic mice. In vitro electrophysiological data showed that overexpression of NR2B specifically in the forebrain region resulted in enhancement of prefrontal cortical long-term potentiation (LTP) but did not alter long-term depression (LTD). The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP. In addition, NR2B transgenic mice exhibited better performance in a set of working memory paradigms including delay no-match-to-place T-maze, working memory version of water maze and odor span task. Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.

Published
2011

14. The Effects of NMDA Subunit Composition on Calcium Influx and Spike Timing-Dependent Plasticity in Striatal Medium Spiny Neurons.

Author

Evans, Rebekah C., Morera-Herreras, Teresa, Yihui Cui, Kai Du, Sheehan, Tom, Kotaleski, Jeanette Hellgren, Venance, Laurent, and Blackwell, Kim T.

Subjects
METHYL aspartate receptors, CALCIUM in the body, NEUROPLASTICITY, NEURONS, LONG-term potentiation, INFORMATION processing
Abstract

Calcium through NMDA receptors (NMDARs) is necessary for the long-term potentiation (LTP) of synaptic strength; however, NMDARs differ in several properties that can influence the amount of calcium influx into the spine. These properties, such as sensitivity to magnesium block and conductance decay kinetics, change the receptor's response to spike timing dependent plasticity (STDP) protocols, and thereby shape synaptic integration and information processing. This study investigates the role of GluN2 subunit differences on spine calcium concentration during several STDP protocols in a model of a striatal medium spiny projection neuron (MSPN). The multi-compartment, multi-channel model exhibits firing frequency, spike width, and latency to first spike similar to current clamp data from mouse dorsal striatum MSPN. We find that NMDAR-mediated calcium is dependent on GluN2 subunit type, action potential timing, duration of somatic depolarization, and number of action potentials. Furthermore, the model demonstrates that in MSPNs, GluN2A and GluN2B control which STDP intervals allow for substantial calcium elevation in spines. The model predicts that blocking GluN2B subunits would modulate the range of intervals that cause long term potentiation. We confirmed this prediction experimentally, demonstrating that blocking GluN2B in the striatum, narrows the range of STDP intervals that cause long term potentiation. This ability of the GluN2 subunit to modulate the shape of the STDP curve could underlie the role that GluN2 subunits play in learning and development. [ABSTRACT FROM AUTHOR]

Published
2012
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