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The Journal of Neuroscience, November 15, 2001, 21(22):8789-8797

An Activity-Dependent Neurotrophin-3 Autocrine Loop Regulates the Phenotype of Developing Hippocampal Pyramidal Neurons before Target Contact

Hassan Boukhaddaoui, Victor Sieso, Frederique Scamps, and Jean Valmier

Institut National de la Santé et de la Recherche Médicale U-432, Universite Montpellier II, 34095 Montpellier, Cedex 5, France

Neurotrophin-3 (NT-3), its cognate receptor trkC, and voltage-gated calcium channels are coexpressed by embryonic pyramidal neurons before target contact, but their functions at this stage of development are still unclear. We show here that, in vitro, anti-NT-3 and anti-trkC antibodies blocked the increase, and NT-3 reversed the decrease in the number of calbindin-D_28k-positive pyramidal neurons induced by, respectively, calcium channel activations and blockades. Similar results were obtained with single-neuron microcultures. In addition, voltage-gated calcium channel inhibition downregulates the extracellular levels of NT-3 in high-density cultures. Moreover, electrophysiological experiments in single-cell cultures reveal a tetrodotoxin-sensitive spontaneous electrical activity allowing voltage-gated calcium channel activation. The mouse NT-3 (/) mutation decreases by 40% the number of developing calbindin-D_28k-positive pyramidal neurons, without affecting neuronal survival, both in vitro and in vivo. Thus, present results strongly support that an activity-dependent autocrine NT-3 loop provides a local, intrinsic mechanism by which, before target contact, hippocampal pyramidal-like neurons may regulate their own differentiation, a role that may be important during early CNS differentiation or after adult target disruption.

Key words: calcium channels; neurotrophin; hippocampus; pyramidal-like neuron; development; autocrine

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21228789-09$05.00/0

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