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Early activity in the developing brain

Khazipov Lab

The objective of our team is to understand the mechanisms that allow the implementation of brain activity at the structural and functional level, and more particularly cortical activity, under physio- and pathophysiological conditions. Through mouse models but also through collaborations with clinicians, we are working to study the mechanisms of activity patterns responsible for brain function. Through a multidisciplinary approach combining brain activity recording, cellular and molecular analyses, we focus on GABAergic neurotransmission and its dichotomy of action according to the level of activation of neural networks.

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Research interests

The objective of our team is to understand the mechanisms that allow the implementation of brain activity at the structural and functional level, and more particularly cortical activity, under physio- and pathophysiological conditions. Through mouse models but also through collaborations with clinicians, we are working to study the mechanisms of activity patterns responsible for brain function. Through a multidisciplinary approach combining brain activity recording, cellular and molecular analyses, we focus on GABAergic neurotransmission and its dichotomy of action according to the level of activation of neural networks.

    Physiological patterns of activity in the developing brain

    Marat MINLEBAEV and Alexis JAKOVLEV

     

    The patterns of activity expressed in the developing cortex (somatosensory and visual) are studied in neonatal rats using electrophysiological and imaging methods. Main hypotheses are verified in premature human neonates in collaboration with A. Kaminska (Paris).

    Developmental changes in GABA signalling

    Claudio Rivera & Aurelie Carabalona

    Developmental Brain Plasticity

    The development of the cerebral cortex is an extremely complex process that is divided into three stages: the proliferation of neuronal progenitors, neuronal migration, and the maturation of neural networks. These different steps require a significant remodeling of the membranes and a dynamic cytoskeleton. Little is known about the molecular mechanisms underlying membrane dynamics during neuronal migration and morphogenesis.
    Cell membrane curvature is a micro morphological change involved in many important cellular processes including endocytosis, exocytosis, and migration. Recent studies demonstrated that the members of an extended protein family, characterized by the presence of a membrane binding and deforming BAR (Bin– Amphiphysin– Rvs) domain function at the interface between the actin cytoskeleton and plasma membrane during the formation of membrane protrusions or invaginations (Doherty and McMahon, 2008; Frost et al., 2009; Takano et al., 2008). These proteins can either generate positive membrane curvature to facilitate the formation of plasma membrane invaginations (e.g. BAR, N-BAR and F-BAR domain proteins) or induce negative membrane curvature to promote the formation of plasma membrane protrusions (I-BAR and IF-BAR domain proteins) (Guerrier et al., 2009; Mattila et al., 2007). These proteins can interact with phosphatidylinositol-4,5-biphosphate (PI(4,5)P2)-rich membranes through their BAR domain and also with actin cytoskeleton through Wasp Homology-2 domain (WH2). Regulation of the actin cytoskeleton is well described in neurons: neuronal migration, axonal and dendritic extension and guidance, dendritic spines formation (Spillane et al., 2011).Indeed, we have recently discovered that Mim, a member of the I-BAR protein family, is fundamental in the membrane bending leading to neuronal filopodia formation, and plays an important role in spine morphology (Saarikangas et al., 2015). However, regulation of the actin cytoskeleton in glial cells has remained poorly understood, and only one glia-specific regulator has been reported so far, the I-BAR protein named Abba (Saarikangas et al., 2008).
    During embryonic development, Abba is highly expressed in the radial glial progenitor cells. Despite Abba’s potential role in neuronal development, very little is known about this protein, including how this protein may lead to neurological pathology (Alazami et al., 2015).

    Our research proposal aims to phenotypically and mechanistically characterize a potentially new syndrome of Abba-dependent brain malformation:
    I) determine the role of Abba on RGP cell fate and brain development.
    II) explore Abba’s potential partners in order to define the molecular mechanism of Abba’s function in brain development.
    II) correlate our results with the human pathology thanks to our ongoing collaboration with clinicians.

    The mechanisms controlling the dynamic changes in the morphology of the cell are starting to be disentangled. This novel and growing field of research is slowly finding its way into developmental neurobiology and will have a profound impact on the way we understand the development of the nervous system.

    Epileptic activity in the developing brain

    Marat MINLEBAEV and Sona JANACKOVA

    Developing brain is prone to seizure, and we try to understand the underlying mechanisms. In parallel, we study network mechanisms of seizures in the cortex obtained from pediatric epileptic patients (Prof. Delalande, Paris), and in the genetically engineered animal models of epilepsy (collaboration with C.Chiron and R.Nabout).

    Post traumatic depression and reactive plasticity

    Christophe Pellegrino & Marine Tessier

    Pathological Brain Plasticity

    Traumatic brain injuries (TBI) are the leading injury-related cause of death and permanent disability. In France, the cerebrovascular accident (CVA) and traumatic insult are the 3rd cause of the mortality after cancers and cardio-vascular diseases. 20% of patients suffering from brain insults die within one month after injury. 75 % of CVA or TBI survivors suffer from the accident their whole life more dramatically, up to 25% will never return to professional life.
    Neurodegeneration, as observed in traumatic brain injury (TBI), is a devastating sequel common to many neuropathological conditions. TBI-induced neurodegeneration is also a major risk factor for epilepsy and major depressive disorders but the mechanisms of post-traumatic depression are poorly understood. A current view is that the brain reacts to pathological insults by activating developmental-like programs for survival, regeneration and replacement of damaged neurons. For instance, we have shown that only after injury mature central neurons become dependent on brain-derived neurotrophic factor (BDNF) trophic support for survival. Interestingly, secondary neurogenesis happening in the hippocampus is a key player in the settling-up of post-traumatic depression. Our aims are:

    I) Study the mechanism of secondary neurogenesis after trauma;
    II) Analyze the neuronal networks and more precisely the GABA neurotransmission in pathological condition;
    III) Study the inflammatory processes at the basis of neuronal death;
    IV) Study the functional consequences of such insults from gene to behavior.

    However the intrinsic mechanisms causing trauma-induced changes in GABAA transmission and consequent rearrangement of post-traumatic neuronal networks are not known. We are interested in understanding how neuro-inflammtion processes could participate in the establishment of long-term consequences of brain trauma through changes in secondary neurogenesis and synaptic integration.
    It is important to realize that the delayed progressive reorganization may stand for the delayed sequelae commonly observed in patients suffering from different forms of brain injury e.g. post-traumatic depression.
    Our team is well known for its achievements in the rapidly expanding research on neuronal ion regulation and its role in signaling, development, plasticity and pathophysiology (Pallud et al., 2014; Pellegrino et al., 2011; Payne et al., 2003; Blaesse et al., 2009; Rivera et al., 2005). Combining molecular biology and electrophysiology, we discovered that the neuronal K-Cl cotransporter, KCC2, plays a key role in the developmental shift of GABAA-mediated neurotransmission from depolarizing to hyperpolarizing (Rivera et al., 1999), and showed that activity-dependent regulation of KCC2 expression requires BDNF signaling (Rivera et al., 2002). The ongoing work has revealed a central role of CCCs in neuronal plasticity and disease mechanisms, particularly epilepsy and trauma (Goubert et al., 2019; Pallud et al., 2014; Huberfeld et al., 2007). Work on the molecular mechanisms underlying these effects has led to the identification of an increasing number of novel, fundamental interactions among growth factors and CCCs (de Koninck Y et al., 2007; Viemari et al., 2011).

    Experimental approaches

    We use a combination of electrophysiology and imaging (intrinsic optical signaling, surface-sensitive imaging) to study brain activity in vivo as well as on acute slices in vitro but also approaches at the cellular and molecular level.

    Keywords

    Neonate, Electroencephalogram, Cortex, Barrel system, Visual, GABA, Seizure, Hypoxia, Pain, Oxytocin, brain plasticity, cognition

    Collaborators

    Prof. G. Buzsaki (Rutgers, USA) on the early brain activity and sensory processing in the behaving neonatal rats;

    Prof. G.L. Holmes (Harvard-Dartmouth, USA) on the paroxysmal activity in the developing brain and the consequences of the neonatal seizures;

    Dr. Anna Kaminska and C.Chiron (Saint Vincent Paul, Paris) on the ontogenesis of human EEG;

    Prof. O.Delalande (Rotschild Fondation, Paris) on the neuronal and network properties of immature human epileptic cortex;

    M. Mazzuca (Necker) and Prof. R.Giniatullin (Kuopio University, Finland) on the analgesic actions of oxytocin at birth;

    Drs. R.Nabout and C.Chiron (Necker, Paris) on the animal model of Dravet syndrome;

    Dr. G Huberfeld (Necker) Epilepsy

    Dr. A. Sirota (Tubingen University, Germany) on the signal processing;

    The team is also involved in a collaboarative project with the Laboratory of the Kazan Federal University, Russia which is supported by the Grant of Government of the Russian Federation.

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    Past members

    Khalilov I (CR1 Inserm)

    Tyzio R (post doc)

    Leinekugel X (post doc)

    Milh M (PhD student)
    Tyzio R. (postdoc)

    Kourdougli N (PhD student)

    Goubert E (PhD student)

    Hanganu I (post doc)

    Colonnese M (post doc)

    Melyan Z (post doc)

    Morozova E (student)

    Lamsa K (post doc)

    Congar P. (PhD student)

    Dzhala V. (postdoc)

    Petanjek Z (postdoc)

    Funding

    - ANR: 2009 Programme MNP « Early activity in the developing brain » (acronym Delta_Brush)

    - ANR Eranet Neuron III

    -Fondation des Gueules Cassées

    -FRM: 2011 team

    - Grant of the Government of the Russian Federation to the Leading Scientists

    Internships

    Our team has open positions for undergraduate students, PhD students and postdoctoral fellows. Applications should be sent to:

    roustem.khazipov@inserm.fr

    claudio.rivera@inserm.fr

    christophe.pellegrino@inserm.fr

     

    Our publications

    Hunting for origins of migraine pain: cluster analysis of spontaneous and capsaicin-induced firing in meningeal trigeminal nerve fibers.

    Zakharov A, Vitale C, Kilinc E, Koroleva K, Fayuk D, Shelukhina I, Naumenko N, Skorinkin A, Khazipov R, Giniatullin R

    Frontiers in cellular neuroscience - Jan 2015

    Ontogeny of kainate-induced gamma oscillations in the rat CA3 hippocampus in vitro.

    Tsintsadze V, Minlebaev M, Suchkov D, Cunningham MO, Khazipov R

    Frontiers in cellular neuroscience - Jan 2015

    Isoflurane suppresses early cortical activity.

    Sitdikova G, Zakharov A, Janackova S, Gerasimova E, Lebedeva J, Inacio AR, Zaynutdinova D, Minlebaev M, Holmes GL, Khazipov R

    Annals of clinical and translational neurology - Jan 2014

    Spontaneous activity in developing sensory circuits: Implications for resting state fMRI.

    Colonnese M, Khazipov R

    NeuroImage - Oct 2012

    Traumatic alterations in GABA signaling disrupt hippocampal network activity in the developing brain.

    Dzhala V, Valeeva G, Glykys J, Khazipov R, Staley K

    The Journal of neuroscience : the official journal of the Society for Neuroscience - Mar 2012

    Newborn Analgesia Mediated by Oxytocin during Delivery.

    Mazzuca M, Minlebaev M, Shakirzyanova A, Tyzio R, Taccola G, Janackova S, Gataullina S, Ben-Ari Y, Giniatullin R, Khazipov R

    Frontiers in cellular neuroscience - Jan 2011

    "Slow activity transients" in infant rat visual cortex: a spreading synchronous oscillation patterned by retinal waves.

    Colonnese MT, Khazipov R

    The Journal of neuroscience : the official journal of the Society for Neuroscience - Mar 2010

    Cholinergic modulation of spindle bursts in the neonatal rat visual cortex in vivo.

    Hanganu IL, Staiger JF, Ben-Ari Y, Khazipov R

    The Journal of neuroscience : the official journal of the Society for Neuroscience - May 2007

    GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations.

    Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R

    Physiological reviews - Oct 2007

    Network mechanisms of spindle-burst oscillations in the neonatal rat barrel cortex in vivo.

    Minlebaev M, Ben-Ari Y, Khazipov R

    Journal of neurophysiology - Jan 2007

    Rapid cortical oscillations and early motor activity in premature human neonate.

    Milh M, Kaminska A, Huon C, Lapillonne A, Ben-Ari Y, Khazipov R

    Cerebral cortex (New York, N.Y. : 1991) - Jul 2007

    Early patterns of electrical activity in the developing cerebral cortex of humans and rodents.

    Khazipov R, Luhmann HJ

    Trends in neurosciences - Jul 2006

    Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery.

    Tyzio R, Cossart R, Khalilov I, Minlebaev M, Hübner CA, Represa A, Ben-Ari Y, Khazipov R

    Science (New York, N.Y.) - Dec 2006

    Early motor activity drives spindle bursts in the developing somatosensory cortex.

    Khazipov R, Sirota A, Leinekugel X, Holmes GL, Ben-Ari Y, Buzsáki G

    Nature - Dec 2004

    Correlated bursts of activity in the neonatal hippocampus in vivo.

    Leinekugel X, Khazipov R, Cannon R, Hirase H, Ben-Ari Y, Buzsáki G

    Science (New York, N.Y.) - Jun 2002

    Ca2+ oscillations mediated by the synergistic excitatory actions of GABA(A) and NMDA receptors in the neonatal hippocampus.

    Leinekugel X, Medina I, Khalilov I, Ben-Ari Y, Khazipov R

    Neuron - Feb 1997