tPa, Stroke and Memory

mri-782457_1920During my thesis, I studied the role of a protease involved in thrombolysis (destruction of blood clot) the tissue-type plasminogen activator (tPA), which is so far the only available treatment for stroke in human (Benchenane et al. Trends Neurosci 2004). But tPA is also capable of cleaving the NR1 sub-unit of the NMDA receptor leading to an increase in calcium influx into the neurons that enhance ischemic neuronal death (Nicole et al., 2001, Fernandez-Monreal et al., J Biol Chem 2004).
The aim is therfore to enhance tPA efficiency in clinical practice by preventing the deleterious effect of tPA in the brain parenchyma without affecting it beneficial effect in the vascular compartment. Two strategies can be used for this purpose:
  1. blockade of the crossing of the blood brain barrier (BBB)
  2. prevent its effect directly in the brain parenchyma.
I have shown that tPA crosses the intact blood-brain barrier and that this was mediated by transcytosis mediated by a receptor: the LDL receptor?related protein (Benchenane et al. Circulation 2005, Benchenane et al., Stroke 2005). However, therapeutic strategy that aim at blocking this receptor is not usable since this receptor is also involve in clearance of the tPA from the blood. This might enhanced the level of circulating tPA which might increase the risk of hemorrhagic transformation.
We then study the action mechanism of tPA in the brain parenchyma. I have shown that vaccination with the recombinant ATD-NR1 (that leads to the generation of antibody which prevent the cleavage of the NMDA receptor by the tPA) was neuroprotective in a model of cerebral ischemia and also prevents the potentiating effect of tPA on NMDA-induced striatal lesion in mice (Benchenane et al., J Cell Sci 2007). This strategy is currently in pre-clinical test, and a patent has been done in collaboration with a pharmaceutical company in order to perform a clinical trial with the co-administration of tPA and the antibody.
Interestingly, tPA is also involved in learning and memory and is induced after protocols of long-term potentiation. We have shown in vivo that the cleavage of the NMDA receptor by the tPA was important for memory since this protocol of vaccination leads to deficits in spatial and social memory (Benchenane et al., J Cell Sci 2007). This shows in vivo that the cleavage of the NMDA receptor is a new way to modulate its function and a new way to mediate the formation of new memory traces.

Oscillations & memory

photo-256887_1920Memory is fundamental to human life. It allows us to acquire and use information to adapt our behavior in response to experience. Memory is not a unitary concept but is composed of multiple memory types that involve different neuroanatomic structures (Squire, 2004). The memory of facts and events, called declarative memory has been shown to rely on the hippocampus for its formation and temporary storage. But in its initial form, the memory trace is still vulnerable to interference. Thus memory traces, initially labile, are remodeled to become durably stored and retrievable. This process has been called memory consolidation. It occurs in two successive periods. First, the trace is stabilized within the hippocampus; a phase that has been called “cellular consolidation” mainly because several cellular and molecular pathways that mediate this consolidation have been discovered. This has been related to the long-term modification of synaptic weight of particular synapses (increase: long-term potentiation (LTP) or decrease: long-term depression, (LTD)). Interestingly, all the treatments that affect LTP also affect long-term memory making LTP the mostly likely cellular correlates of long-term memory. But this is not the final stage, indeed the memory trace undergoes a second step of consolidation by being transferred in neocortical sites. This has been called “systemic consolidation” since it relies on communication between different brain structures.

Brain states and memory processes

In fact, this hypothesis of consolidation that had been proposed in the 70’s by theoretical works (Marr, 1970; McClelland et al., 1995) but has received many several experimental validations and extensions. Of the most important is its relation to internal brain states. Indeed the brain is not a passive structure that receives and processes external information but is the site of different modes of activity, mainly revealed by extracellular recordings of the electroencephalogram, local field potential and action potentials. Early observation of EEG identified different oscillation mode that were different across conscious states especially when comparing rest and sleep and those oscillation patterns have been called brain states. EEG during conscious, waking behavior demonstrated low-amplitude, “desynchronized” patterns, while sleep and unconscious states were associated with large irregular fluctuation of the local filed potential. Subsequent studies showed that these brain states differ according to the structure of recording and tried to link each pattern of oscillations to behavioral or conscious states.
To summarize, three main brain states have been clearly identify and characterize: 1) the theta state corresponding to awake activity (mostly when the rat is moving) showing desynchronized activity in the cortex and theta oscillation (5-10 Hz) in the hippocampus, 2) the slow-wave sleep (SWS): showing large irregular activity (slow oscillation) in the cortex while the hippocampus shows large depolarization in the stratum radiatum (sharp waves) associated with short lasting burst of oscillations at 200Hz in the pyramidal layer (ripples), 3) the REM sleep: (for rapid-eye movement sleep) , also called paradoxal sleep since brain activity is very similar to awake activity i.e. desynchronized activity in the cortex and theta oscillations in the hippocampus. Of course, there are mainly other oscillatory patterns observed in the cortex, and their full characterization and the identification of their cognitive correlates constitute an intense topic, especially concerning attention.
Concerning learning and memory, it has been proposed that each sequential phases of memory (encoding, consolidation) are related to different internal brain states. The two-stage memory consolidation theory postulates that encoding occurs during hippocampal theta oscillations, and consolidation is supposed to take place during SWS, involving reactivation that occurs during the sharp-waves-ripples complexes (SPW-Rs) (Buzsaki, 1989).

During my post-doctoral stage, I have provided further information that validate and extend several of these hypotheses.

Encoding in the theta states and consolidation during ripples in the hippocampal-prefrontal network: role of the dopamine

First, I found that the two-stage memory consolidation theory does not only rely on the sole hippocampus (as initially proposed) but can also be extended to the hippocampal-prefrontal network. I have shown that during learning, coherence in the theta band between the hippocampus (Hpc) and the prefrontal cortex (Pfc) occurs when the rat was able to solve the behavioral task and more precisely at time of reward prediction. At this point, during elevated Hpc-Pfc theta coherence and upon new learning, there are profound modifications of the neuronal network within the PFc. Hpc theta-modulated Pfc cells shift phase preference leading to the formation of Pfc cell assemblies. Activity synchronization then lead to synaptic plasticity and to the consolidation of assembly-related memory traces, as shown by the enhanced replay of high-coherence related assemblies during post-training SPW-Rs. These findings, taken together, point to a possible mechanism wherein theta coherence would help to determine which information is reactivated during sleep and thus consolidated in long-term memory. Thus, the Hpc/neocortical axis, deeply implicated in memory consolidation (Marr, 1970; Buzsaki, 1989; McClelland et al., 1995), may also be responsible during memory encoding, for the selection of the relevant information to be retained, under dopaminergic control. Indeed, most of the results obtained in vivo after learning at the time of reward prediction (Hpc-Pfc theta coherence, phase shift in the Pfc) can be mimicked in anesthetized rats with dopamine injection in the Pfc (Benchenane et al. Neuron 2010, Benchenane et al. Curr Opinion Neurobiol 2011, Peyrache, Khamassi, Benchenane et al. Nat Neurosci 2009, Battaglia, Benchenane et al., Trends Cogn Sci 2011)

Causal role of the sharp-waves ripples in memory consolidation.

The second main finding of my post-doctoral studies was to identify the causal role of ripples on learning and memory consolidation. Indeed, this link was at that time only based on correlative studies. By using closed loop between neuronal activity and stimulation (classically used in brain machine interface), we showed that selective ripples suppression during sleep following spatial task impaired learning (Girardeau*, Benchenane* et al., Nat Neurosci 2009, co-authorship). Reactivations appeared therefore to be necessary to memory consolidation as subsequent performance depends on those ripples event.

Karim Benchenane

Full permanent CNRS Researcher (CR1)
Currently: Leader of ATIP/Avenir team Memory Oscillations and Brain states at ESPCI ParisTech
Research focus: Brain states, oscillation and memory processes
AERES evaluation for the project : A+

in Laboratory of Neurobiology – UMR 7637 CNRS ESPCI

2009-2011: Team Navigation, Memory and Aging, in the Laboratory of Neurobiology of Adaptative Processes, University Pierre and Marie Curie, UMR 7102, Paris, France.
Research focus: Brain states, oscillation and memory processes
2006-2009: Post-doctoral scholar at the LPPA Collège de France, CNRS UMR 7152, Paris, France.
PI: Sidney Wiener.
Research focus: Role of sleep in memory consolidation and interaction between hippocampus and prefrontal cortex.

2005:Post-doctoral scholar at the CMBN, Rutgers University, Newark, USA. PI: Esther Nimchinsky
Research focus: Study of the role of astrocytes in neuronal plasticity with two-photon microscopy.

Graduate Studies

2004: PhD in Molecular and Cellular Neuroscience in UMR 6551, University de Caen – CNRS, Caen, France.
Award date Dec, 21th 2004. PhD advisors Pr Denis Vivien and Dr Omar Touzani.
Research focus: Interaction between the tissue-type plasminogen activator and the NMDA receptor: involvement in ischemic neuronal death and in learning and memory.

To read my thesis

Undergraduate Studies

• Bachelor, Master in Biology (2000)
• Bachelor in Psychology (2000)
• Preparatory classes for competitive exams to enter french ‘Grandes Ecoles’ (Mathematics & Physics)

Supervision of students

  • Gaetan de Lavilléon (PhD student; co-direction with Laure Rondi-Reig);
  • Marie Lacroix (PhD student, co-direction with André Klarsfeld);
  • Sophie Bagur (Master, ENS Ulm, 2013)
  • Lisa Roux (PhD; principal advisor: Christian Giaume, 2010-2011);
  • Noelia Do Carmo Blanco (Master 2nd year, 2013);
  • Matthieu Komora (Master 1st year, 2013);
  • Parvaneh Adibpour (Master 1st year, 2012);
  • Mathieu Tihy (Master 1st year, 2011);
  • Raphaelle Kulis (Engineer ESPCI 1st year, 2012);
  • Baptiste Guédon (Engineer Ecole Centrale Paris 3rd year, 2012);
  • Karim El Kanbi (Engineer Ecole Centrale Paris 3rd year, 2012);
  • Joachim Zentic (Engineer Ecole Centrale Paris 3rd year, 2012).


  • 2016: ERC Consolidator Grant
  • 2013: Equipe ATIP/Avenir (280 000 € , PI Karim Benchenane)
  • 2013: Programme Emergence de la ville de Paris (300 000 €, PI Karim Benchenane)
  • 2013: Funding ITMO Grant (co-PI with Pr Marion Leboyer). Title: Sleep, Inflammation and bipolar disorders (7500 €)
  • 2013: Funding ANR Grant (Title: AstroSleep, 74809 €, PI: Christian Giaume)
  • 2013: Funding by the ESPCI (team installation) (75000 €)
  • 2010: Funding Neuroscience and Computational Neuroinformatic, Neuro-IC (35 000 €).
  • Principal investigator of the Project entitled: « MMN-P3B: A cortical column model to account for the mismatch negativity in the auditory pathway » (in collaboration with Dr. Stanislas Dehaene and Dr. Alain Destexhe).
  • PhD fellowship from the French ministry of Research

Awards and prizes

• Award  “Prix la Recherche” (2011):
Best article in Neuroscience for 2010 delivered by the journal La Recherche, for the study Benchenane K, Peyrache A, Khamassi M, Tierney PL, Gioanni Y, Battaglia FP, Wiener SI. (2010) Coherent theta oscillations and reorganization of spike timing in the hippocampal-prefrontal network upon learning. Neuron, June 24;66(6):921-36.

• Award AXA–French Academy of Science (2010):
“Major advances in biological studies in France presented by the authors” for the article: Girardeau G*,Benchenane K*, Wiener SI, Buzsáki G, Zugaro MB. (2010) « Selective suppression of hippocampal ripples perturbes learning in a spatial reference memory task ». Nat. Neurosci, Oct;12(10):1222-23. (*equal contribution)

Teaching activities

  • Responsible of a module in the specialty « Ingénierie Biomédicale et Innovation en Neurosciences (IBIN) of the Master BME, University Paris Descartes – Paris Tech (2012-2013)
  • Lecturer in 1st and 2nd year of Master in  University Pierre and Marie Curie (2010 -2012)
  • Lecturer in 2nd year of Master in University Paris-Sud (2012).
  • Lecturer in Engineer school ESPCI-Paris Tech, Paris, France. (2012)
  • Lecturer in 2nd year of Master CogMaster (University Paris Descartes, ENS, EHESS), Paris (2012)
  • Participation to the organization of the 5th national forum of cognitive science (2006)

Valorization and patent

During my PhD, I have shown that a protocol of vaccination that leads to the generation of antibodies that prevent the cleavage of the NMDA receptor by the tissue-type plasminogen activator prevent the deleterious effect of tPA in the brain parenchyma while leaving its beneficial proteolytic action in the blood unaffected(Benchenane et al., J Cell Sci 2007).
This strategy is currently in pre-clinical test, and a patent has been done in collaboration with a pharmaceutical company (Paion) in order to perform a clinical trial with the co-administration of tPA and the antibody.
Patent EP2289542; EUROPEAN PATENT APPLICATION, EP 2 289 542 A1, Treatment of neurological or neurodegenerative disorders. Application number: 09011149.3

Other academic activities

Reviewer for Brain Research, Neuroscience, PLOS One. Circulation, Stroke…

Research Coordination

• Member of the Scientific Council of the French Research Group on Sleep
• Member of the Research Group on Neuroscience of memory (NeuroMem) GDR 2905
• Member of the Research Group on multiple-electrode recording (Multi- electrode Systems and Signal Processing for Neural Networks) GDR 2904

Collaborators (classified by alphabetical order)

Angelo Arleo, Université Pierre et Marie Curie, Paris, France
Thierry Bal, CNRS, Gif sur Yvette, France
Francesco P. Battaglia, Amsterdam University, Amsterdam, The Netherlands
Gyorgy Buzsaki, Rutgers University, Newark, USA
Stanislas Dehaene, INSERM, CEA, Collège de France, Paris, France
Alain Destexhe, CNRS, Gif sur Yvette, France
Christian Giaume, INSERM, Collège de France, Paris, France
Yves Gioanni, Collège de France, Paris, France
Benoît Girard, Université Pierre et Marie Curie, Paris, France
Mark Humphreys, Sheffield University, Sheffield, United Kingdom
Adrien Peyrache, Rutgers University, Newark, USA
Emmanuel Procyk, INSERM, Stem cells and Brain Research Institute, Bron, France
Nathalie Rouach, INSERM, Collège de France, Paris, France
Denis Vivien, INSERM Université de Caen, Caen, France

tree-307231_1280Lab websites
Laboratory of Neurobiology, CNRS UMR 7637, at ESPCI ParisTech (Paris, France)

My Neurotree page
My Academia page

Le Prix La Recherche

Karim Benchenane receives in October 2011 the Price « La Recherche en Neurosciences » for his article:

Benchenane K. et al. « Coherent theta oscillations and reorganization of spike timing in the hippocampal-prefrontal network upon learning », Neuron 2010 June24;66(6):921-36.