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The Journal of Neuroscience, February 4, 2009, 29(5):1414-1423; doi:10.1523/JNEUROSCI.3697-08.2009

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Cellular/Molecular
The GABAB1a Isoform Mediates Heterosynaptic Depression at Hippocampal Mossy Fiber Synapses

Nicole Guetg,1,3 * Riad Seddik,1 * Réjan Vigot,1 Rostislav Turecek,1 Martin Gassmann,1 Kaspar E. Vogt,2 Hans Bräuner-Osborne,1,4 Ryuichi Shigemoto,5,6,7 Oliver Kretz,3 Michael Frotscher,3 Ákos Kulik,3 and Bernhard Bettler1

1Department of Biomedicine, Institute of Physiology, Pharmazentrum, and 2Division of Pharmacology and Neurobiology, Biozentrum, University of Basel, 4056 Basel, Switzerland, 3Institute of Anatomy and Cell Biology, Department of Neuroanatomy, University of Freiburg, 79104 Freiburg, Germany, 4Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark, 5Division of Cerebral Structure, National Institute for Physiological Sciences, and 6Department of Physiological Sciences, The Graduate University of Advanced Studies (Sokendai), Myodaiji, Okazaki 444-8787, Japan, and 7Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan

Correspondence should be addressed to either of the following: Bernhard Bettler, Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland, Email: bernhard.bettler{at}unibas.ch; or Ákos Kulik, Institute of Anatomy and Cell Biology, Department of Neuroanatomy, University of Freiburg, Albertstrasse 17, D-79104 Freiburg, Germany, E-mail: Email: akos.kulik{at}anat.uni-freiburg.de

GABAB receptor subtypes are based on the subunit isoforms GABAB1a and GABAB1b, which associate with GABAB2 subunits to form pharmacologically indistinguishable GABAB(1a,2) and GABAB(1b,2) receptors. Studies with mice selectively expressing GABAB1a or GABAB1b subunits revealed that GABAB(1a,2) receptors are more abundant than GABAB(1b,2) receptors at glutamatergic terminals. Accordingly, it was found that GABAB(1a,2) receptors are more efficient than GABAB(1b,2) receptors in inhibiting glutamate release when maximally activated by exogenous application of the agonist baclofen. Here, we used a combination of genetic, ultrastructural and electrophysiological approaches to analyze to what extent GABAB(1a,2) and GABAB(1b,2) receptors inhibit glutamate release in response to physiological activation. We first show that at hippocampal mossy fiber (MF)-CA3 pyramidal neuron synapses more GABAB1a than GABAB1b protein is present at presynaptic sites, consistent with the findings at other glutamatergic synapses. In the presence of baclofen at concentrations ≥1 µM, both GABAB(1a,2) and GABAB(1b,2) receptors contribute to presynaptic inhibition of glutamate release. However, at lower concentrations of baclofen, selectively GABAB(1a,2) receptors contribute to presynaptic inhibition. Remarkably, exclusively GABAB(1a,2) receptors inhibit glutamate release in response to synaptically released GABA. Specifically, we demonstrate that selectively GABAB(1a,2) receptors mediate heterosynaptic depression of MF transmission, a physiological phenomenon involving transsynaptic inhibition of glutamate release via presynaptic GABAB receptors. Our data demonstrate that the difference in GABAB1a and GABAB1b protein levels at MF terminals is sufficient to produce a strictly GABAB1a-specific effect under physiological conditions. This consolidates that the differential subcellular localization of the GABAB1a and GABAB1b proteins is of regulatory relevance.

Key words: GABA(B); GABA-B; metabotropic; hippocampus; presynaptic inhibition; heteroreceptor

Received Aug. 5, 2008; revised Dec. 2, 2008; accepted Dec. 31, 2008.

Correspondence should be addressed to either of the following: Bernhard Bettler, Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland, Email: bernhard.bettler{at}unibas.ch; or Ákos Kulik, Institute of Anatomy and Cell Biology, Department of Neuroanatomy, University of Freiburg, Albertstrasse 17, D-79104 Freiburg, Germany, E-mail: Email: akos.kulik{at}anat.uni-freiburg.de






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