Differential expression and function of GABAB receptor isoforms in the hippocampal dentate gyrus

Joshua Foster, Ian kitchen, Ying Chen. University of Surrey, Guildford, Surrey, United Kingdom.

The GABAB receptors are heterodimeric G-protein coupled receptors comprising of GABAB1 and GABAB2 subunits. Activation of GABAB receptors results in synaptic inhibition in neural circuits. Two major isoforms of the GABAB1 subunit, GABAB1a and GABAB1b, form the two main receptor subtypes with GABAB2 subunits. Differential expression and function of the GABAB1 isoforms has been demonstrated in the CA1 and CA3 areas of the hippocampus, with the GABAB1a containing receptors being the exclusive heteroreceptor at glutamate terminals. In the dentate gyrus, however, activation of the GABAB receptors has been shown to cause excitation in granule cells by reducing a recurrent inhibition (Mott et al., 1989). The aim of this study is to investigate the role of GABAB receptor subtypes in the modulation of synaptic transmission in the dentate gyrus.

Adult male wild-type (WT) BALB/c mice and their littermate transgenic mice lacking the GABAB1a (1a-/-) or GABAB1b (1b-/-) were used for immunohistochemical and electrophysiological investigation. Immunoperoxidase labelling of the GABAB1 and GABAB2 receptor subunits was performed on coronal brain sections using antibodies directed against the GABAB1 and GABAB2 subunits. GABAB receptor functions were studied in hippocampal slices. Using a MED64 multielectrode array system (Chen et al., 2006), the perforant path was stimulated in the molecular layer of the dentate gyrus and field excitatory postsynaptic potentials (fEPSP) and population spikes (PS) were recorded in the molecular and granule cell layers, respectively.

Baclofen (10 μM) did not affect the fEPSP slope or amplitude in all genotypes, demonstrating that the perforant path-granule cell excitatory transmission was not altered by the activation of GABAB receptors. However, baclofen (10 μM) increased the absolute area of the PSs recorded in the granule cell layers in all genotypes (percentage change from baseline: WT 49.77 ± 5.58%, n = 5; 1a-/- 30.27 ± 6.15%, n = 5; 1b-/- 75.09 ± 3.86%, n = 4), the 1b-/- responses were found to differ from both WT and 1a-/- (one-way ANOVA with Tukey post-hoc test; WT vs. 1b-/- p < 0.05 and 1a-/- vs. 1b-/- p < 0.001).This agrees with a marked reduction of GABAB subunit staining in the dentate gyrus of 1b -/- mice. Overall, our data suggests that the GABAB receptor subtypes may differently modulate recurrent inhibition in the dentate gyrus.

Chen et al. (2006) JPET 317:1170-7.
Mott et al. (1989) JPET 249:721-5.

Funding for this project is provided by the BBSRC. The transgenic mice used in this investigation were a gift from Prof. B. Bettler, University of Basel.