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Brain-Derived Neurotrophic Factor and Neurotrophin-3 Enhance Somatostatin Gene Expression through a Likely Direct Effect on Hypothalamic Somatostatin Neurons¹

Laboratoire de Plasticité Cérébrale (F.R., B.R., L.T.-A.), EP 628 CNRS and U336 INSERM (G.A.), Université de Montpellier 2, 34095 Montpellier, Cedex 5, France

Address all correspondence and requests for reprints to: Dr. Lucia Tapia-Arancibia, Laboratoire de Plasticité Cérébrale, EP 628 CNRS, Université de Montpellier 2, Place Eugène Bataillon, 34095 Montpellier Cédex 5, France. E-mail: aranci{at}crit.univ-montp2.fr

Although neurotrophins (NTs) have been extensively studied as neuronal survival factors in some areas of the central nervous system, little is known about their function or cellular targets in the hypothalamus. To understand their functional significance and sites of action on hypothalamic neurons, we examined the effects of their cognate ligands on neuropeptide content and messenger RNA (mRNA) expression in somatostatin neurons present in fetal rat hypothalamic cultures. Treatments were performed in defined insulin-free medium between days 6 and 8 of culture, since the maximal effects of NTs on somatostatin content and mRNA expression were observed after 48-h incubations. Brain-derived neurotrophic factor and NT-3, but not nerve growth factor, induced a dose-dependent increase in somatostatin content, which was influenced by plating density. The same treatment increased somatostatin mRNA and immunostaining intensity of somatostatin neurons, but had no effect on the number of these labeled neurons. The increased levels of somatostatin (peptide and mRNA) induced by NTs were not blocked by tetrodotoxin or by glutamate receptor antagonists, suggesting that endogenous neurotransmitters (e.g. glutamate) were not involved in these effects. In contrast, the stimulatory effects were completely blocked by K-252a, an inhibitor of tyrosine kinase (Trk) receptors, whereas the less active analog K-252b was ineffective. Double-labeling studies demonstrated that both TrkB or TrkC receptors were located on somatostatin neurons. Our results show that, in rat hypothalamic cultures, brain-derived neurotrophic factor, and NT-3 have a potent stimulatory effect on peptide synthesis in somatostatinergic neurons, likely through direct activation of TrkB and TrkC receptors.

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