title: Dynamic Changes from Depolarizing to Hyperpolarizing GABAergic Actions during Giant Depolarizing Potentials in the Neonatal Rat Hippocampus.
abstract: During development, GABA exerts depolarizing action on immature neurons and, acting in synergy with glutamate, drives giant depolarizing potentials (GDPs) in the hippocampal network. Yet, blockade of the GABA(A) receptors transforms GDPs to epileptiform discharges suggesting dual, both excitatory and inhibitory, actions of GABA in the immature hippocampal network. However, the nature of this dualism in early GABA actions is poorly understood. Here we characterized the dynamics of synaptic currents mediated by GABA(A) and glutamate receptors through an estimation of the changes in their conductance and driving forces in neonatal rat CA3 pyramidal cells during GDPs. We found that depolarizing GABAergic and glutamatergic currents act in synergy at the GDPs' onset. However, during the peak of the population discharge, the inward synaptic current was essentially mediated by glutamate receptors whereas GABA currents transiently switched their direction from depolarizing to hyperpolarizing as a result of neuronal depolarization above the GABA(A) reversal potential. Thus, the action of GABA on CA3 pyramidal cells dynamically changes during GDPs from excitatory at the GDPs' onset to inhibitory at the GDPs' peak. We propose that the dynamic changes in GABA actions occurring during GDPs enable GABAergic interneurons not only to initiate the discharge of pyramidal cells but also to control excitation in the recurrent CA3 network preventing epileptiform synchronization.
  
  
  CONCLUSIONS
  During development GABA exerts a depolarizing action on immature neurons. However, at the network level the effects of GABA are complex involving both excitatory and inhibitory actions. Here we show that GABA actions critically depend on the network state. Although GABA depolarizes neurons at rest and at the onset of population bursts, it transiently becomes hyperpolarizing at the peak of the population bursts. These dynamic changes in GABA actions enable GABAergic interneurons not only to initiate the network discharge but also to control excitation to prevent epileptiform synchronization.
authors.affiliation: INMED, INSERM U-901 and Aix-Marseille University, Marseille, 13273, France, and Laboratory of Neurobiology, Kazan Federal University, Kazan, 42008, Russia.
authors.forename: Ilgam
authors.initials: I
authors.lastname: Khalilov
authors.affiliation: INMED, INSERM U-901 and Aix-Marseille University, Marseille, 13273, France, and Laboratory of Neurobiology, Kazan Federal University, Kazan, 42008, Russia.
authors.forename: Marat
authors.initials: M
authors.lastname: Minlebaev
authors.affiliation: Laboratory of Neurobiology, Kazan Federal University, Kazan, 42008, Russia.
authors.forename: Marat
authors.initials: M
authors.lastname: Mukhtarov
authors.affiliation: INMED, INSERM U-901 and Aix-Marseille University, Marseille, 13273, France, and Laboratory of Neurobiology, Kazan Federal University, Kazan, 42008, Russia roustem.khazipov@inserm.fr.
authors.forename: Roustem
authors.initials: R
authors.lastname: Khazipov
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000502:physiology*; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D006096:Gramicidin / Q000494:pharmacology; D007395:Interneurons / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009415:Nerve Net / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D006096:Gramicidin; D005680:gamma-Aminobutyric Acid
keywords: GABA; development; giant depolarizing potentials; hippocampus; network; synchronization