Differential compartmentalization and distinct functions of GABAB receptor variants

Réjan Vigot; Samuel Barbieri; Hans Bräuner-Osborne; Rostislav Turecek; Ryuichi Shigemoto; Yan-Ping Zhang; Rafael Luján; Laura H Jacobson; Barbara Biermann; Jean-Marc Fritschy; Claire-Marie Vacher; Matthias Müller; Gilles Sansig; Nicole Guetg; John F Cryan; Klemens Kaupmann; Martin Gassmann; Thomas G Oertner; Bernhard Bettler

doi:10.1016/j.neuron.2006.04.014

Differential compartmentalization and distinct functions of GABAB receptor variants

Réjan Vigot, Samuel Barbieri, Hans Bräuner-Osborne, Rostislav Turecek, Ryuichi Shigemoto, Yan-Ping Zhang, Rafael Luján, Laura H Jacobson, Barbara Biermann, Jean-Marc Fritschy, Claire-Marie Vacher, Matthias Müller, Gilles Sansig, Nicole Guetg, John F Cryan, Klemens Kaupmann, Martin Gassmann, Thomas G Oertner, Bernhard Bettler

229 Citations (Scopus)

Abstract

GABAB receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). Molecular diversity in the GABAB system arises from the GABAB1a and GABAB1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats that is unique to GABAB1a. Using a combined genetic, physiological, and morphological approach, we now demonstrate that GABAB1 isoforms localize to distinct synaptic sites and convey separate functions in vivo. At hippocampal CA3-to-CA1 synapses, GABAB1a assembles heteroreceptors inhibiting glutamate release, while predominantly GABAB1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABAB1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABAB1a in distal axons, suggesting that the sushi repeats, a conserved protein interaction motif, specify heteroreceptor localization. The constitutive absence of GABAB1a but not GABAB1b results in impaired synaptic plasticity and hippocampus-dependent memory, emphasizing molecular differences in synaptic GABAB functions.

Original language	English
Journal	Neuron
Volume	50
Issue number	4
Pages (from-to)	589-601
ISSN	0896-6273
DOIs	https://doi.org/10.1016/j.neuron.2006.04.014
Publication status	Published - 18 May 2006

Keywords

Animals
Blotting, Northern
Excitatory Postsynaptic Potentials
Hippocampus
Immunohistochemistry
Memory
Mice
Mice, Mutant Strains
Microscopy, Confocal
Microscopy, Electron, Transmission
Neuronal Plasticity
Neurons
Protein Isoforms
Receptors, GABA-B
Synapses
Transfection

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10.1016/j.neuron.2006.04.014

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Vigot, R., Barbieri, S., Bräuner-Osborne, H., Turecek, R., Shigemoto, R., Zhang, Y.-P., Luján, R., Jacobson, L. H., Biermann, B., Fritschy, J.-M., Vacher, C.-M., Müller, M., Sansig, G., Guetg, N., Cryan, J. F., Kaupmann, K., Gassmann, M., Oertner, T. G., & Bettler, B. (2006). Differential compartmentalization and distinct functions of GABAB receptor variants. Neuron, 50(4), 589-601. https://doi.org/10.1016/j.neuron.2006.04.014

Vigot, R, Barbieri, S, Bräuner-Osborne, H, Turecek, R, Shigemoto, R, Zhang, Y-P, Luján, R, Jacobson, LH, Biermann, B, Fritschy, J-M, Vacher, C-M, Müller, M, Sansig, G, Guetg, N, Cryan, JF, Kaupmann, K, Gassmann, M, Oertner, TG & Bettler, B 2006, 'Differential compartmentalization and distinct functions of GABAB receptor variants', Neuron, vol. 50, no. 4, pp. 589-601. https://doi.org/10.1016/j.neuron.2006.04.014

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abstract = "GABAB receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). Molecular diversity in the GABAB system arises from the GABAB1a and GABAB1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats that is unique to GABAB1a. Using a combined genetic, physiological, and morphological approach, we now demonstrate that GABAB1 isoforms localize to distinct synaptic sites and convey separate functions in vivo. At hippocampal CA3-to-CA1 synapses, GABAB1a assembles heteroreceptors inhibiting glutamate release, while predominantly GABAB1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABAB1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABAB1a in distal axons, suggesting that the sushi repeats, a conserved protein interaction motif, specify heteroreceptor localization. The constitutive absence of GABAB1a but not GABAB1b results in impaired synaptic plasticity and hippocampus-dependent memory, emphasizing molecular differences in synaptic GABAB functions.",

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AU - Vigot, Réjan

AU - Barbieri, Samuel

AU - Bräuner-Osborne, Hans

AU - Turecek, Rostislav

AU - Shigemoto, Ryuichi

AU - Zhang, Yan-Ping

AU - Luján, Rafael

AU - Jacobson, Laura H

AU - Biermann, Barbara

AU - Fritschy, Jean-Marc

AU - Vacher, Claire-Marie

AU - Müller, Matthias

AU - Sansig, Gilles

AU - Guetg, Nicole

AU - Cryan, John F

AU - Kaupmann, Klemens

AU - Gassmann, Martin

AU - Oertner, Thomas G

AU - Bettler, Bernhard

PY - 2006/5/18

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N2 - GABAB receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). Molecular diversity in the GABAB system arises from the GABAB1a and GABAB1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats that is unique to GABAB1a. Using a combined genetic, physiological, and morphological approach, we now demonstrate that GABAB1 isoforms localize to distinct synaptic sites and convey separate functions in vivo. At hippocampal CA3-to-CA1 synapses, GABAB1a assembles heteroreceptors inhibiting glutamate release, while predominantly GABAB1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABAB1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABAB1a in distal axons, suggesting that the sushi repeats, a conserved protein interaction motif, specify heteroreceptor localization. The constitutive absence of GABAB1a but not GABAB1b results in impaired synaptic plasticity and hippocampus-dependent memory, emphasizing molecular differences in synaptic GABAB functions.

AB - GABAB receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). Molecular diversity in the GABAB system arises from the GABAB1a and GABAB1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats that is unique to GABAB1a. Using a combined genetic, physiological, and morphological approach, we now demonstrate that GABAB1 isoforms localize to distinct synaptic sites and convey separate functions in vivo. At hippocampal CA3-to-CA1 synapses, GABAB1a assembles heteroreceptors inhibiting glutamate release, while predominantly GABAB1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABAB1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABAB1a in distal axons, suggesting that the sushi repeats, a conserved protein interaction motif, specify heteroreceptor localization. The constitutive absence of GABAB1a but not GABAB1b results in impaired synaptic plasticity and hippocampus-dependent memory, emphasizing molecular differences in synaptic GABAB functions.

KW - Animals

KW - Blotting, Northern

KW - Excitatory Postsynaptic Potentials

KW - Hippocampus

KW - Immunohistochemistry

KW - Memory

KW - Mice

KW - Mice, Mutant Strains

KW - Microscopy, Confocal

KW - Microscopy, Electron, Transmission

KW - Neuronal Plasticity

KW - Neurons

KW - Protein Isoforms

KW - Receptors, GABA-B

KW - Synapses

KW - Transfection

U2 - 10.1016/j.neuron.2006.04.014

DO - 10.1016/j.neuron.2006.04.014

M3 - Journal article

C2 - 16701209

SN - 0896-6273

VL - 50

SP - 589

EP - 601

JO - Neuron

JF - Neuron

IS - 4

ER -

Differential compartmentalization and distinct functions of GABAB receptor variants

Abstract

Keywords

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