Research interest

The goal of our project is to elucidate how neurotrophic factors and chloride homeostasis contribute to developmental forms of GABAergic synaptic plasticity during physiological conditions and in animal models of neurological disorders. γ-amino butyric acid (GABA) is a key regulator of brain function and plays a central role in its development (Ben-Ari et al., 2007). GABAergic interneurons regulate neuronal excitability, synaptic integration and network oscillation dynamics and as such are crucial for many cognitive functions. As a result, defective GABA levels and GABAergic transmission are strongly associated with cognitive dysfunction and neurological disorders. Understanding the factors that modulate the development and efficacy of the GABAergic system is thus of particular interest because it may provide key insights into disease states and potential treatments. The project combines molecular and cellular biology, electrophysiology, biochemistry and imaging on primary cultures of hippocampal neurons and acute brain slices.

Project includes three specific aims:

  • aAim 1: Trophic role of leptin on GABAergic synaptogenesis and plasticity (Principal investigator J.L. Gaiarsa).
  • bAim 2: Dynamic regulation of GABAA-receptors at synaptic sites (Principal investigator C. Porcher).
  • cAim 3: Regulation of chloride homeostasis (Principal investigator I.Medina).
a

Aim 1: Trophic role of leptin on GABAergic synaptogenesis and plasticity (Principal investigator J.L. Gaiarsa).

Leptin, the protein product of the obese (ob) gene is a circulating hormone synthetized predominantly by the adipose tissue, which plays a pivotal role in the control of energy balance through its action on specific hypothalamic nuclei. However accumulating evidence indicates that leptin acts beyond this classical regulatory role and may function as an important developmental signal in the hypothalamus and other brain areas, including the cortex and hippocampus. Our objective is to understand whether and how leptin contributes to the development of hippocampal GABAergic synapses in vivo (Guimond et al., 2014).

b

Aim 2: Dynamic regulation of GABAA-receptors at synaptic sites (Principal investigator C. Porcher).

The fast synaptic inhibition in adult mammalian brains mediated through GABA type A receptors (GABAA-Rs) is important for many cognitive functions. For efficient synaptic transmission, GABAA-Rs need to be localized to and anchored at postsynaptic sites in precise apposition to presynaptic nerve terminals that release the neurotransmitter GABA. Our objective is to understand how the Brain-derived neurotrophic factor (BDNF) regulates the subcellular targeting of GABAA-Rs to the neuronal plasma membrane in physiological and pathophysiological conditions (langlois et al., 2013; Riffault et al., 2014).

c

Aim 3: Regulation of chloride homeostasis (Principal investigator I.Medina).

The inhibitory strength of GABAergic neurotransmission depends on the intracellular Cl- concentration. While the proteins mediating Cl- transport including channels, transporters, and exchangers are now largely known, the genes and pathways that regulate them to establish context-specific activity are incompletely characterized. The neuronal potassium-chloride co-transporter KCC2 is one of the molecules effectively controlling intracellular Cl- and adjusting the inhibitory strength of GABA. The KCC2 is implicated in numerous neurological disorders including different forms of epilepsy, neuropathic pain, post-surgical complication and autism spectrum disorders. Among molecules controlling KCC2 function are BDNF and several kinases and phosphatases. In the project we are studying signaling pathways (including BDNF-dependent) involved in control of the KCC2 activity and downstream GABAergic neurotransmission during neuronal development under physiological conditions and in models of epilepsy and autism (Medina et al 2014).

Experimental approaches

Preparations (hippocampal acute slices, intact hippocampi, dissociated and organotypic slice cultures), électrophysiology (Field, sharp and patch clamp recordings), Imagery (Time lapse video fluorescent microscopy), Cell biology (neuronal transfections and infections, RT-PCR), Morphology (immuno-histochemistry, confocal neuronal reconstruction).

Key words

Neurotrophin, BDNF, leptin, synaptogenesis, GABA, development, epilepsy, neuron, KCC2, Chlore, synapses.

Collaborators

Dr. G. Wayman Department of Veterinary and Comparative Anatomy, Physiology and Pharmacology, Washington State University, USA.

Dr. C Hubner University Hospital Jena, Friedrich Schiller University Jena, Germany

 

Past members

Pr. L. Zagrean zagrean@univermed-cdgm.ro
Dr. H.A. McLean heather.mclean@u-psud.fr
Dr. N. Villeneuve
Dr. P. Gubellini paolo.gubellini@ibdml.univmed.fr
Dr. P. Tosetti Patrizia.TOSETTI@cec.eu.int
Dr. I. Colin-Le Brun Isabelle.LeBrun@ujf-grenoble.fr
Dr. O. Caillard caillard.o@jean-roche.univ-mrs.fr
Dr.Y.Salyha, Institute of animal physiology, Ukraine
Dr. A. Ivanov anton.ivanov@inserm.fr
Dr. S.Rama sylvain.rama@univ-amu.fr
Dr. I.Chudotvorova Freiburg University
Dr. A Langlois
Dr. D. Guimond
Dr. P.Friedel Yale University

Fundings

ANR, CNRS, INSERM, FRM, LFCE

Join our team

Our team has open positions for undergraduate students, PhD students and postdoctoral fellows. Applications should be sent to jean-Luc Gaiarsa

Publications

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