Roles of GABAB receptor subtypes in presynaptic auto- and heteroreceptor function regulating GABA and glutamate...

Gamma-Aminobutyric acid B (GABA B) receptors are heterodimers composed of two subunits GABA B(1) and GABA B(2), the former existing in two isoforms GABA B(1a) and GABA B(1b). The contributions of individual receptor subunits and isoforms to GABA B auto- and heteroreceptor functions were investigated, using release experiments in cortical slice preparations from corresponding knockout mice. Presynaptic GABA B autoreceptors are located on GABAergic terminals and inhibit GABA release, whereas presynaptic GABA B 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 GABA B(1)-/- mice. The amount of [3H]GABA released per pulse was unaffected by the stimulation frequency in slices from GABA B(1)-/- and GABA B(2)-/- demonstrating a loss of GABA B autoreceptor function in these knockout animals. The GABA B receptor agonist baclofen was ineffective in modulating glutamate release in cortical slices from GABA B(2)-/- mice, showing that heteroreceptor function was abolished as well. Next we investigated knockout mice for the two predominant GABA B(1) isoforms expressed in brain, GABA B(1a) and GABA B(1b). In cortical, hippocampal and striatal slices from both GABA B(1a)-/- and GABA B(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 GABA B autoreceptor function. By contrast, the efficacy of baclofen to inhibit glutamate release was substantially reduced in GABA B(1a)-/-, but essentially unaltered in GABA B(1b)-/- mice. Our data suggest that functional GABA B heteroreceptors regulating glutamate release are predominantly, but not exclusively composed of GABA B(1a) and GABA B(2) subunits.