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035P Queen Elizabeth II Conference Centre London
BPS Winter Meeting 2011



GABAB Receptor Subtypes Differentially Affect Synaptic Inhibition in the Dentate Gyrus

Joshua D Foster1, Ian Kitchen1, Bernhard Bettler2, Ying Chen1. 1FHMS, University of Surrey, Guildford, UK, 2Pharmazentrum, University of Basel, Basel, Switzerland.


GABAB receptors are G-protein-coupled receptors for the inhibitory neurotransmitter GABA. Two functional subtypes are expressed in the brain by combining a GABAB1 isoform, GABAB1a or GABAB1b, with a GABAB2 subunit. The GABAB(1a,2) receptors exclusively exert presynaptic inhibition on glutamate synapses, but both subtypes reduce GABA release. It is, however, unclear whether the subtypes are co-expressed or differentially localised on inhibitory pathways. We assessed the hypothesis that GABAB subtypes may differentially modulate synaptic inhibition by selective expression in inhibitory pathways.

We examined the function and localisation of GABAB receptors in the dentate gyrus of GABAB1 isoform knockout mice using multielectrode electrophysiological recordings and immunohistochemical labelling. In the rat dentate gyrus, the predominant function of GABAB receptors is the enhancement of granule cell (GC) excitability via presynaptic inhibition of GABA release. Here, in murine dentate gyrus, GABAB receptor activation by the agonist, baclofen (10 µM), did not alter the excitatory synaptic transmission measured by the field excitatory postsynaptic potential (p > 0.05), but increased the population spike of GCs in both the wild-type (142.7 ± 6.1% of control, n = 7) and knockout mice (136.1 ± 4.3% (n = 9) for GABAB1a-/- mice and 161.7 ± 9.4% (n = 6) for GABAB1b-/- mice). The significantly larger effect in GABAB1b-/- mice (p < 0.001, repeated two-way ANOVA) indicated a more powerful effect by GABAB(1a,2) receptors. In addition, all baclofen-induced effects were prevented by the GABAB receptor antagonist CGP55845 (1 µM, p < 0.001, repeated two-way ANOVA), or GABAA receptor antagonist bicuculline (10 µM, n = 6 mice from each genotype), showing a mechanism via GABAB receptor-mediated reduction of GABA release. Immunohistochemical labelling of GABAB1 and GABAB2 subunits highlighted cell body staining in hilar neurons and neuropil labelling in the molecular and GC layers. However, in GABAB1a-/- mice neuropil staining in the inner molecular and GC layers was reduced together with the number of immunopositive hilar neurons at the hilus-GC border zone (by 24.3%, p < 0.05, one-way ANOVA with Tukey’s multiple comparisons). In GABAB1b-/- mice, in contrast, reduction of neuropil staining was found in the outer molecular layers, and the number of immunolabeled hilar neurons decreased at both the border zone (by 28.7%, p < 0.05) and in deep layers (25.9%, p < 0.05). GABAB(1a,2) receptors may, therefore, predominantly modulate GABA release from hilar projections onto the perisomatic and proximal dendritic regions of the GCs and thereby exert more powerful disinhibition than GABAB(1b,2) receptors, which control the distal dendritic fields. By selective expression in interneurons and their projections, GABAB receptor subtypes may, therefore, differentially modulate synaptic inhibition.

The work was supported by the BBSRC.