JOURNAL ARTICLES
GABAergic stimulation switches from enhancing to repressing BDNF expression in rat hippocampal neurons during maturation in vitro
B. Berninger, S. Marty, F. Zafra, M. da Penha Berzaghi, H. Thoenen, D. Lindholm
Development 1995 121: 2327-2335;

Summary

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the adult mammalian central nervous system. However, GABA depolarizes immature rat hippocampal neurons and increases intracellular Ca2+ ([Ca2+]i). Here we show, that GABA and the GABAA receptor agonist muscimol induce c-Fos immunoreactivity and increase BDNF mRNA expression in embryonic hippocampal neurons cultured for 5 days. In contrast, after 3 weeks in culture, GABA and muscimol failed to induce c-fos and BDNF expression. Fura-2 fluorescence microscopy revealed that muscimol produces a dihydropyridine-sensitive transient increase in [Ca2+]i, comparable to the effect of the non-NMDA receptor agonist kainic acid in neurons cultured for 5 days, but not in 3-week-old cultures. The increase in c-Fos immunoreactivity and BDNF mRNA levels by GABA were dependent upon the activation of voltage-gated Ca2+ channels, as shown using the L-type specific Ca2+ channel blocker nifedipine. The differential regulation of c-fos and BDNF expression by GABA and muscimol in developing and mature hippocampal neurons is due to a switch in the ability of GABAA receptors to activate voltage-gated Ca2+ channels. These observations support the hypothesis that GABA might have neurotrophic effects on embryonic or perinatal hippocampal neurons, which are mediated by BDNF.

Reference

    1. Bading H.,
    2. Ginty D. D.,
    3. Greenberg M. E.
    (1993) Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. Science 260, 181–186
    OpenUrlAbstract/FREE Full Text
    1. Barbin G.,
    2. Pollard H.,
    3. Gaiarsa J. L.,
    4. Ben-Ari Y.
    (1993) Involvment of GABAAreceptors in the outgrowth of cultured hippocampal neurons. Neurosci. Lett 152, 150–154
    OpenUrlCrossRefPubMedWeb of Science
    1. Barde Y.-A.,
    2. Edgar D.,
    3. Thoenen H.
    (1982) Purification of a new neurotrophic factor from mammalian brain. EMBO J 1, 549–553
    OpenUrlPubMedWeb of Science
    1. Barde Y.-A.
    (1990) The nerve growth factor family. Prog. Growth Factor Res 2, 237–248
    OpenUrlCrossRefPubMed
    1. Behar T. N.,
    2. Schaffner A. E.,
    3. Colton C. A.,
    4. Somogy R.,
    5. Olah Z.,
    6. Lehel C.,
    7. Barker J. L.
    (1993) GABA-induced chemokinesis and NGF-induced chemotaxis of embryonic spinal cord neurons. J. Neurosci 14, 29–38
    OpenUrlAbstract
    1. Berninger B.,
    2. García D. E.,
    3. Inagaki N.,
    4. Hahnel C.,
    5. Lindholm D.
    (1993) BDNF and NT-3 induce intracellular Ca2+elevation in hippocampal neurones. NeuroReport 4, 1303–1306
    OpenUrlCrossRefPubMedWeb of Science
    1. Berzaghi M. P.,
    2. Cooper J.,
    3. Castren E.,
    4. Zafra F.,
    5. Sofroniew M.,
    6. Thoenen H.,
    7. Lindholm D.
    (1993) Cholinergic regulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) but not neurotrophin-3 (NT-3) mRNA levels in the developing rat hippocampus. J. Neurosci 13, 3818–3826
    OpenUrlAbstract
    1. Castren E.,
    2. Pitkänen M.,
    3. Sirviö J.,
    4. Parsadanian A.,
    5. Lindholm D.,
    6. Thoenen H.,
    7. Riekkinen P. J.
    (1993) The induction of LTP increases BDNF and NGF mRNA but decreases NT-3 mRNA in the dentate gyrus. NeuroReport 4, 895–898
    OpenUrlPubMedWeb of Science
    1. Cherubini E.,
    2. Rovira C.,
    3. Gaiarsa J. L.,
    4. Corradetti R.,
    5. Ben-Ari Y.
    (1990) GABA mediated excitation in immature rat CA3 hippocampal neurons. Int. J. Dev. Neurosci 8, 481–490
    OpenUrlCrossRefPubMedWeb of Science
    1. Cherubini E.,
    2. Gaiarsa J. L.,
    3. Ben-Ari Y.
    (1991) GABA: an excitatory transmitter in early postnatal life. Trends Neurosci 14, 515–519
    OpenUrlCrossRefPubMedWeb of Science
    1. Chomczynski P.,
    2. Sacchi N.
    (1987) Single-step method of RNA isolation by acid guanidinum thiocyanate-phenol-chloroform extraction. Analyt. Biochem 162, 156–159
    OpenUrlCrossRefPubMedWeb of Science
    1. Cole A. J.,
    2. Saffen D. W.,
    3. Baraban J. M.,
    4. Worley P. F.
    (1989) Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340, 474–476
    OpenUrlCrossRefPubMedWeb of Science
    1. Connor J. A.,
    2. Tseng H.-Y.,
    3. Hockberger P. E.
    (1987) Depolarization-and transmitter-induced changes in intracellular Ca2+ of rat cerebellar granule cells in explant cultures. J. Neurosci 7, 1384–1400
    OpenUrlAbstract
    1. Croll S. D.,
    2. Wiegand S. J.,
    3. Anderson K. D.,
    4. Lindsay R. M.,
    5. Nawa H.
    (1994) Regulation of neuropeptides in adult rat forebrain by the neurotrophins BDNF and NGF. Eur. J. Neurosci 6, 1343–1353
    OpenUrlCrossRefPubMedWeb of Science
    1. Davies A. M.
    (1994) The role of neurotrophins in the developing nervous system. J. Neurobiol 25, 1334–1348
    OpenUrlCrossRefPubMedWeb of Science
    1. Dugich-Djordjevic M. M.,
    2. Tocco G.,
    3. Willoughby D. A.,
    4. Najm I.,
    5. Pasinetti G.,
    6. Thompson R. F.,
    7. Baudry M.,
    8. Lapchak P. A.,
    9. Hefti F.
    (1992) BDNF mRNA expression in the developing rat brain following kainic acid induced seizure activity. Neuron 8, 1127–1138
    OpenUrlCrossRefPubMedWeb of Science
    1. Ernfors P.,
    2. Lee K.-F.,
    3. Jaenisch R.
    (1994) Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368, 147–150
    OpenUrlCrossRefPubMedWeb of Science
    1. Fiszman M. L.,
    2. Novotny E. A.,
    3. Lange G. D.,
    4. Barker J. L.
    (1990) Embryonic and early postnatal hippocampal cells respond to nanomolar concentrations of muscimol. Dev. Brain Res 53, 186–193
    OpenUrlCrossRefPubMed
    1. Fritschy J.-M.,
    2. Paysan J.,
    3. Enna A.,
    4. Mohler H.
    (1994) Switch in the expression of rat GABAA-receptor subtypes during postnatal development: an immunohistochemical study. J. Neurosci 14, 5302–.
    OpenUrlAbstract
    1. Gall C. M.,
    2. Isackson P. J.
    (1989) Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 245, 758–761
    OpenUrlAbstract/FREE Full Text
    1. Gosh A.,
    2. Carnahan J.,
    3. Greenberg M. E.
    (1994) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263, 1618–1623
    OpenUrlAbstract/FREE Full Text
    1. Götz R.,
    2. Köster R.,
    3. Winkler C.,
    4. Raulf F.,
    5. Lottspeich F.,
    6. Schartl M.,
    7. Thoenen H.
    (1994) Neurotrophin-6 is a new member of the nerve growth factor family. Nature 372, 266–269
    OpenUrlCrossRefPubMedWeb of Science
    1. Grynkiewicz G.,
    2. Poenie M.,
    3. Tsien R. Y.
    (1985) A new generation of Ca2+indicators with greatly improved fluorescence properties. J. Biol. Chem 260, 3440–3450
    OpenUrlAbstract/FREE Full Text
    1. Hofer M.,
    2. Pagliusi S. R.,
    3. Hohn A.,
    4. Leibrock J.,
    5. Barde Y.-A.
    (1990) Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J 9, 2459–2464
    OpenUrlPubMedWeb of Science
    1. Hosokawa Y.,
    2. Sciancalepore M.,
    3. Stratta F.,
    4. Martina M.,
    5. Cherubini E.
    (1994) Developmental changes in spontaneous GABAA-mediated synaptic events in rat hippocampal CA3 neurons. Eur. J. Neurosci 6, 805–813
    OpenUrlCrossRefPubMedWeb of Science
    1. Hyman C.,
    2. Hofer M.,
    3. Barde Y.-A.,
    4. Juhasz M.,
    5. Yancopoulos G. D.,
    6. Squinto S. P.,
    7. Lindsay R. M.
    (1991) BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 350, 230–232
    OpenUrlCrossRefPubMedWeb of Science
    1. Ip N. Y.,
    2. Li Y.,
    3. Yancopoulos G. D.,
    4. Lindsay R. M.
    (1993) Culturedhippocampal neurons show responses to BDNF, NT-3, and NT-4, but not NGF. J. Neurosci 13, 3394–3405
    OpenUrlAbstract
    1. Jones K. R.,
    2. Fariñas I.,
    3. Backus C.,
    4. Reichardt L. F.
    (1994) Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell 76, 989–999
    OpenUrlCrossRefPubMedWeb of Science
    1. Leibrock J.,
    2. Lottspeich F.,
    3. Hohn A.,
    4. Hofer M.,
    5. Hengerer B.,
    6. Masiakowski P.,
    7. Thoenen H.,
    8. Barde Y.-A.
    (1989) Molecular cloning and expression of brain-derived neurotrophic factor. Nature 341, 149–152
    OpenUrlCrossRefPubMedWeb of Science
    1. Lin M.-H.,
    2. Takahashi M. P.,
    3. Takahashi Y.,
    4. Tsumoto T.
    (1994) Intracellular calcium increase induced by GABA in visual cortex of fetal and neonatal rats and its disappearance with development. Neurosci. Res 20, 85–94
    OpenUrlCrossRefPubMedWeb of Science
    1. Lindefors N.,
    2. Ernfors P.,
    3. Falkenberg T.,
    4. Persson H.
    (1992) Septal cholinergic afferents regulate expression of brain-derived neurotrophic factor and-nerve growth factor mRNA in rat hippocampus. Exp. Brain Res 88, 78–90
    OpenUrlCrossRefPubMedWeb of Science
    1. Lindholm D.,
    2. Dechant G.,
    3. Heisenberg C.-P.,
    4. Thoenen H.
    (1993) Brain-derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate-induced neurotoxicity. Eur. J. Neurosci 5, 1455–1464
    OpenUrlCrossRefPubMedWeb of Science
    1. Maisonpierre P. C.,
    2. Belluscio L.,
    3. Friedman B.,
    4. Alderson R.,
    5. Wiegand S. J.,
    6. Furth M. E.,
    7. Lindsay R. M.,
    8. Yancopoulos G. D.
    (1990) NT3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron 5, 501–507
    OpenUrlCrossRefPubMedWeb of Science
    1. Marsh H. N.,
    2. Scholz W. K.,
    3. Lamballe F.,
    4. Klein R.,
    5. Nanduri V.,
    6. Barbacid M.,
    7. Palfrey H. C.
    (1993) Signal transduction events mediated by the BDNF receptor gp145 trk Bin primary hippocampal pyramidal cell culture. J. Neurosci 13, 4281–4292
    OpenUrlAbstract
    1. Misgeld U.,
    2. Deisz R. A.,
    3. Dodt H. U.,
    4. Lux H. D.
    (1986) The role of chloride transport in postsynaptic inhibition of hippocampal neurons. Science 232, 1413–1415
    OpenUrlAbstract/FREE Full Text
    1. Mody I.,
    2. De Koninck Y.,
    3. Otis T. S.,
    4. Soltesz I.
    (1994) Bridging the cleft at GABA synapses in the brain. Trends Neurosci 17, 517–525
    OpenUrlCrossRefPubMedWeb of Science
    1. Morgan J. I.,
    2. Curran T.
    (1986) Role of ion flux in control of c-fos expression. Nature 322, 552–555
    OpenUrlCrossRefPubMedWeb of Science
    1. Morgan J. I.,
    2. Cohen D. R.,
    3. Hempstead J. L.,
    4. Curran T.
    (1987) Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237, 192–197
    OpenUrlAbstract/FREE Full Text
    1. Mueller A. L.,
    2. Taube J. S.,
    3. Schwartzkroin P. A.
    (1984) Development of hyperpolarizing inhibitory postsynaptic potentials and hyperpolarizing response to-aminobutyric acid in rabbit hippocampus studied in vitro. J. Neurosci 4, 860–867
    OpenUrlAbstract
    1. Nawa H.,
    2. Pelleymounter M. A.,
    3. Carnahan J.
    (1994) Intraventricular administration of BDNF increases neuropeptide expression in newborn rat brain. J. Neurosci 14, 3751–3765
    OpenUrlAbstract
    1. Poulter M. O.,
    2. Barker J. L.,
    3. O`Carroll A.-M.,
    4. Lolait S. J.,
    5. Mahan L. C.
    (1992) Differential and transient expression of GABAAreceptor-subunit mRNA in the developing rat CNS. J. Neurosci 12, 2888–2900
    OpenUrlAbstract
    1. Reichling D. B.,
    2. Kyrozis A.,
    3. Wang J.,
    4. MacDermott A. B.
    (1994) Mechanisms of GABA and glycine depolarization-induced calcium transients in rat dorsal horn neurons. J. Physiol. (Lond.) 476, 411–421
    OpenUrlCrossRefPubMedWeb of Science
    1. Segal M.
    (1993) GABA induces unique rise of [Ca2+]iin cultured rat hippocampal neurons. Hippocampus 3, 229–238
    OpenUrlCrossRefPubMedWeb of Science
    1. Sheng M.,
    2. Greenberg M. E.
    (1990) The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 4, 477–485
    OpenUrlCrossRefPubMedWeb of Science
    1. Snider W. D.
    (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638
    OpenUrlCrossRefPubMedWeb of Science
    1. Wang J.,
    2. Reichling D. B.,
    3. Kyrozis A.,
    4. MacDermott A. B.
    (1994) Developmental loss of GABA-and glycine-induced depolarization and Ca2+transients in embryonic rat dorsal horn neurons in culture. Eur. J. Neurosci 6, 1275–1280
    OpenUrlCrossRefPubMedWeb of Science
    1. Wu W.,
    2. Ziskind-Conhaim L.,
    3. Sweet M. A.
    (1992) Early development of glycine-and GABA-mediated synapses in rat spinal cord. J. Neurosci 12, 3935–3945
    OpenUrlAbstract
    1. Yuste R.,
    2. Katz L. C.
    (1991) Control of postsynaptic Ca2+influx in developing neocortex by excitatory and inhibitory neurotransmitters. Neuron 6, 33–344
    1. Zafra F.,
    2. Hengerer B.,
    3. Leibrock J.,
    4. Thoenen H.,
    5. Lindholm D.
    (1990) Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J 9, 3545–3550
    OpenUrlPubMedWeb of Science
    1. Zafra F.,
    2. Castren E.,
    3. Thoenen H.,
    4. Lindholm D.
    (1991) Interplay between glutamate and-aminobutyric acid transmitter systems in the regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc. Natl. Acad. Sci. USA 88, 10037–10041
    OpenUrlAbstract/FREE Full Text
    1. Zafra F.,
    2. Lindholm D.,
    3. Castren E.,
    4. Hartikka J.,
    5. Thoenen H.
    (1992) Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. J. Neurosci 12, 4793–4799
    OpenUrlAbstract
Back to top

 Download PDF

Email
GABAergic stimulation switches from enhancing to repressing BDNF expression in rat hippocampal neurons during maturation in vitro
B. Berninger, S. Marty, F. Zafra, M. da Penha Berzaghi, H. Thoenen, D. Lindholm
Development 1995 121: 2327-2335;
Permalink:
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Alerts

Article navigation

Other journals from The Company of Biologists

Spotlights

In this issue we turn the spotlight onto considerations of ethics in developmental biology.

The status of the human embryo in various religions

William Neaves briefly describes how several different religions perceive the human embryo, and considers how this might influence their view of human embryological research.

'Homunculus' by Nicolas Hartsoeker in 1694, depicting a little infant inside the head of a human sperm

Interspecies chimeras for human stem cell research

Hideki Masaki and Hiromitsu Nakauchi discuss the potential of interspecies chimeras for human stem cell research, and the significant barriers and ethical issues surrounding their generation.

Featured article – A framework for understanding the roles of miRNAs in animal development

Hierarchical organization of the gene regulatory networks that control embryonic development

Chiara Alberti and Luisa Cochella review how different classes of miRNAs fit into the hierarchy of gene regulatory networks that control development, from early embryogenesis to cell differentiation.

Featured article – A toolkit for GFP-mediated tissue-specific protein degradation in C. elegans

Confocal images of 1.5-fold C. elegans embryos expressing GIP-2::GFP

Karen Oegema and colleagues reveal a simple method to target GFP-tagged proteins for proteasomal degradation enables spatially controlled protein elimination in C. elegans.

Transfer to Biology Open

If your submission to Development is unsuccessful, did you know you can transfer your paper and any reviews directly to our sister journal, Biology Open? The majority of papers transferred with reviews are accepted for publication. Find out how here.