Abstract
Γ-Aminobutyric acid B (GABAB) receptors are heterodimers composed of two subunits GABAB(1) and GABAB(2), the former existing in two isoforms GABAB(1a) and GABAB(1b). The contributions of individual receptor subunits and isoforms to GABAB auto- and heteroreceptor functions were investigated, using release experiments in cortical slice preparations from corresponding knockout mice. Presynaptic GABAB autoreceptors are located on GABAergic terminals and inhibit GABA release, whereas presynaptic GABAB heteroreceptors control the release of other neurotransmitters (e.g. glutamate). Neither baclofen nor the selective antagonist CGP55845 at maximally active concentrations affected [3H]GABA release in slices from GABAB(1)−/− mice. The amount of [3H]GABA released per pulse was unaffected by the stimulation frequency in slices from GABAB(1)−/− and GABAB(2)−/− demonstrating a loss of GABAB autoreceptor function in these knockout animals. The GABAB receptor agonist baclofen was ineffective in modulating glutamate release in cortical slices from GABAB(2)−/− mice, showing that heteroreceptor function was abolished as well. Next we investigated knockout mice for the two predominant GABAB(1) isoforms expressed in brain, GABAB(1a) and GABAB(1b). In cortical, hippocampal and striatal slices from both GABAB(1a)−/− and GABAB(1b)−/− mice, the frequency dependence of [3H]GABA released per pulse was maintained, suggesting that both isoforms participate or can substitute for each other in GABAB autoreceptor function. By contrast, the efficacy of baclofen to inhibit glutamate release was substantially reduced in GABAB(1a)−/−, but essentially unaltered in GABAB(1b)−/− mice. Our data suggest that functional GABAB heteroreceptors regulating glutamate release are predominantly, but not exclusively composed of GABAB(1a) and GABAB(2) subunits.
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Abbreviations
- AOAA:
-
Aminooxyacetic acid
- GDH:
-
Glutamate dehydrogenase
- Ko:
-
Knockout
- l-trans-PDC:
-
l-trans-pyrrolidine-2,4-dicarboxylic acid
- Wt:
-
Wildtype
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Acknowledgments
The authors wish to thank Dr. Johannes Mosbacher for his comments on the manuscript. We are grateful to Ms. Dominique Monna and Mr. Jean-Jacques Feldtrauer for their expert technical assistance.
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An erratum to this article can be found at http://dx.doi.org/10.1007/s00702-009-0206-0
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Waldmeier, P.C., Kaupmann, K. & Urwyler, S. Roles of GABAB receptor subtypes in presynaptic auto- and heteroreceptor function regulating GABA and glutamate release. J Neural Transm 115, 1401–1411 (2008). https://doi.org/10.1007/s00702-008-0095-7
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DOI: https://doi.org/10.1007/s00702-008-0095-7