Neuronal activity and brain-derived neurotrophic factor regulate the density of inhibitory synapses in organotypic slice cultures of postnatal hippocampus.
Hippocampal interneurons inhibit pyramidal neurons through the release of the neurotransmitter GABA. Given the importance of this inhibition for the proper functioning of the hippocampus, the development of inhibitory synapses must be tightly regulated. In this study, the possibility that neuronal activity and neurotrophins regulate the density of GABAergic inhibitory synapses was investigated in organotypic slice cultures taken from postnatal day 7 rats. In hippocampal slices cultured for 13 d in the presence of the GABA(A) receptor antagonist bicuculline, the density of glutamic acid decarboxylase (GAD) 65-immunoreactive terminals was increased in the CA1 area when compared with control slices. Treatment with the glutamate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione decreased the density of GAD65-immunoreactive terminals in the stratum oriens of CA1. These treatments had parallel effects on the density of GABA-immunoreactive processes. Electron microscopic analysis after postembedding immunogold labeling with antibodies against GABA indicated that bicuculline treatment increased the density of inhibitory but not excitatory synapses. Application of exogenous BDNF partly mimicked the stimulatory effect of bicuculline on GAD65-immunoreactive terminals. Finally, antibodies against BDNF, but not antibodies against nerve growth factor, decrease the density of GAD65-immunoreactive terminals in bicuculline-treated slices. Thus, neuronal activity regulates the density of inhibitory synapses made by postnatal hippocampal interneurons, and BDNF could mediate part of this regulation. This regulation of the density of inhibitory synapses could represent a feedback mechanism aimed at maintaining an appropriate level of activity in the developing hippocampal networks.
Marty
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S
Institut National de la Santé et de la Recherche Médicale U106, H opital de la Salpêtrière, Pavillon de l'Enfance et de l'Adolescence, 75651 Paris cedex 13, France.marty@chups.jussieu.fr.
Wehrlé
R
R
Sotelo
C
C
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002452:Cell Count; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007395:Interneurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D009433:Neural Inhibition / Q000502:physiology*; D020933:Neurotrophin 3 / Q000378:metabolism / Q000494:pharmacology; D009940:Organoids / Q000166:cytology / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D011859:Radiography; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D007527:Isoenzymes; D020933:Neurotrophin 3; D011810:Quinoxalines; D005680:gamma-Aminobutyric Acid; C056723:FG 9041; D020932:Nerve Growth Factor; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D001640:Bicuculline