GABA(B) receptor activation triggers BDNF release and promotes the maturation of GABAergic synapses.
GABA, the main inhibitory neurotransmitter in the adult brain, has recently emerged as an important signal in network development. Most of the trophic functions of GABA have been attributed to depolarization of the embryonic and neonatal neurons via the activation of ionotropic GABA(A) receptors. Here we demonstrate a novel mechanism by which endogenous GABA selectively regulates the development of GABAergic synapses in the developing brain. Using whole-cell patch-clamp recordings on newborn mouse hippocampi lacking functional GABA(B) receptors (GABA(B)-Rs) and time-lapse fluorescence imaging on cultured hippocampal neurons expressing GFP-tagged brain-derived neurotrophic factor (BDNF), we found that activation of metabotropic GABA(B) receptors (GABA(B)-Rs) triggers secretion of BDNF and promotes the development of perisomatic GABAergic synapses in the newborn mouse hippocampus. Because activation of GABA(B)-Rs occurs during the characteristic ongoing physiological network-driven synaptic activity present in the developing hippocampus, our results reveal a new mechanism by which synaptic activity can modulate the development of local GABAergic synaptic connections in the developing brain.
Fiorentino
Hervé
H
Institut de Neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale, Unité 901, and Université de La Méditerranée, 13273 Marseille Cedex 09, France.
Kuczewski
Nicola
N
Diabira
Diabe
D
Ferrand
Nadine
N
Pangalos
Menelas N
MN
Porcher
Christophe
C
Gaiarsa
Jean-Luc
JL
D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology; D018408:Patch-Clamp Techniques / Q000379:methods; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000172:deficiency / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D010721:Phosphinic Acids; D011412:Propanolamines; D011810:Quinoxalines; D018080:Receptors, GABA-B; D026941:Sodium Channel Blockers; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D049452:Green Fluorescent Proteins; C085075:CGP 55845A; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; C056639:2-amino-5-phosphopentanoic acid; D050882:CREB-Binding Protein; C013411:biocytin; D014633:Valine; D008239:Lysine