Emerging neurotrophic role of GABAB receptors in neuronal circuit development

The proper development of highly organized structures in the central nervous system is a complex process during which key events – neurogenesis, migration, growth, differentiation, and synaptogenesis – have to take place in an appropriate manner to create functional neuronal networks. It is now well established that GABA, the main inhibitory neurotransmitter in the adult mammalian brain, plays more than a classical inhibitory role and can function as an important developmental signal early in life. GABA binds to chloride-permeable ionotropic GABA(A) receptors and to G-protein-coupled GABA(B) receptors (GABA(B)-Rs). Although most of the trophic actions of GABA have been attributed to the activation of GABA(A) receptors, recent advances show that GABA(B)-Rs also regulate fundamental steps of network development. This review summarizes some of the recent progress about the neurotrophic role of GABA(B)-Rs to neuronal development

Etude du developpement physiologique et morphologique de la region CA_3 de l'hippocampe de rat

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : T 80316 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Mechanism of BDNF Modulation in GABAergic Synaptic Transmission in Healthy and Disease Brains

In the mature healthy mammalian neuronal networks, γ-aminobutyric acid (GABA) mediates synaptic inhibition by acting on GABAA and GABAB receptors (GABAAR, GABABR). In immature networks and during numerous pathological conditions the strength of GABAergic synaptic inhibition is much less pronounced. In these neurons the activation of GABAAR produces paradoxical depolarizing action that favors neuronal network excitation. The depolarizing action of GABAAR is a consequence of deregulated chloride ion homeostasis. In addition to depolarizing action of GABAAR, the GABABR mediated inhibition is also less efficient. One of the key molecules regulating the GABAergic synaptic transmission is the brain derived neurotrophic factor (BDNF). BDNF and its precursor proBDNF, can be released in an activity-dependent manner. Mature BDNF operates via its cognate receptors tropomyosin related kinase B (TrkB) whereas proBDNF binds the p75 neurotrophin receptor (p75NTR). In this review article, we discuss recent finding illuminating how mBDNF-TrkB and proBDNF-p75NTR signaling pathways regulate GABA related neurotransmission under physiological conditions and during epilepsy

Rôle de l'activité synaptique dans la maturation fonctionnelle des synapses gabaergiques de l'hippocampe en développement

L'activité neuronale est un facteur essentiel dans le développement des réseaux neuronaux. Dans l'hippocampe, la majorité de l'activité développementale est présente sous la forme de bouffées d'activité synchrone, les GDPs (Giant Depolarizing Potentials), dont la fonction n'est pas clairement établie. J'expose dans ce travail de thèse deux mécanismes distincts liant activité et maturation synaptique. Dans le premier, l'activation endogène des récepteurs GABAB au cours des GDPs entraîne une libération de BDNF (Brain Derived Neurotrophic Factor) qui est nécessaire au développement d'une population de synapses GABAergiques. L'autre décrit le rôle joué par l'activité synaptique glutamatergique spontanée dans une forme de plasticité des synapses GABAergiques, également liée à la libération de BDNF; les GDPs ne sont cependant pas impliqués dans ce phénomène. Ces deux mécanismes décrivent donc des aspects complémentaires de la maturation synaptique fonctionnelle dans l'hippocampeNeuronal activity is required for the correct development of neuronal networks. In the hippocampus, most of the developmental activity exists as bursts of synchronous activity known as GDPs (Giant Depolarizing Potentials), whose function remains to be determined. I present in my thesis two distinct mechanisms that establish a link between activity and synaptic maturation. I first show that endogenous activation of GABAB receptors during GDPs induces a BDNF (Brain Derived Neurotrophic Factor) release that is necessary for the development of a population of GABAergic synapses. Next, I show that spontaneous glutamatergic activity plays a role in the plasticity of GABAergic synapses, whose induction also required BDNF release; GDPs are not involved in this phenomenon though. Thus, both mechanisms are complementary aspects of the functional synaptic maturation in the developing hippocampusAIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Activity-dependent dendritic secretion of brain-derived neurotrophic factor modulates synaptic plasticity

International audienc

Activity-dependent dendritic secretion of brain-derived neurotrophic factor modulates synaptic plasticity

International audienc

Mechanism of BDNF Modulation in GABAergic Synaptic Transmission in Healthy and Disease Brains

International audienceIn the mature healthy mammalian neuronal networks, γ-aminobutyric acid (GABA) mediates synaptic inhibition by acting on GABA A and GABA B receptors (GABA A R, GABA B R). In immature networks and during numerous pathological conditions the strength of GABAergic synaptic inhibition is much less pronounced. In these neurons the activation of GABA A R produces paradoxical depolarizing action that favors neuronal network excitation. The depolarizing action of GABA A R is a consequence of deregulated chloride ion homeostasis. In addition to depolarizing action of GABA A R, the GABA B R mediated inhibition is also less efficient. One of the key molecules regulating the GABAergic synaptic transmission is the brain derived neurotrophic factor (BDNF). BDNF and its precursor proBDNF, can be released in an activity-dependent manner. Mature BDNF operates via its cognate receptors tropomyosin related kinase B (TrkB) whereas proBDNF binds the p75 neurotrophin receptor (p75 NTR). In this review article, we discuss recent finding illuminating how mBDNF-TrkB and proBDNF-p75 NTR signaling pathways regulate GABA related neurotransmission under physiological conditions and during epilepsy

Long-term potentiation of GABAergic synaptic transmission in neonatal rat hippocampus.

International audience1. The plasticity of GABAergic synapses was investigated in neonatal rat hippocampal slices obtained between postnatal days 3 and 6 using intracellular recording techniques. Ionotropic glutamate receptor antagonists were present throughout the experiments to isolate GABAA receptor-mediated postsynaptic potentials (GABAA PSPs) or currents (GABAA PSCs). 2. Repetitive depolarizing pulses (20 pulses, 0.5 s duration, at 0.1 Hz, each pulse generating 4-6 action potentials) induced a long-term potentiation in the slope and amplitude of the evoked GABAA PSPs and GABAA PSCs. 3. Long-term potentiation was prevented by intracellular injection of the calcium chelator BAPTA (50 mM), or when the voltage-dependent calcium channels blockers Ni2+ (50 microM) and nimodipine (10 microM) were bath applied. 4. Repetitive depolarizing pulses induced a persistent (over 1 h) increase in the frequency of spontaneous GABAA PSCs. 5. Repetitive depolarizing pulses induced a long-lasting increase in the frequency of miniature GABAA PSCs, without altering their amplitude or decay-time constant. 6. It is concluded that the postsynaptic activation of voltage-dependent calcium channels leads to a long-term potentiation of GABAergic synaptic transmission in neonatal rat hippocampus. This form of plasticity is expressed as an increase in the probability of GABA release or in the number of functional synapses, rather than as an upregulation of postsynaptic GABAA receptor numbers or conductance at functional synapses