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. 2013 Apr;168(8):1808-19.
doi: 10.1111/bph.12073.

GABAB receptor subtypes differentially modulate synaptic inhibition in the dentate gyrus to enhance granule cell output

Joshua D Foster  1 , Ian Kitchen, Bernhard Bettler, Ying Chen
Affiliations

GABAB receptor subtypes differentially modulate synaptic inhibition in the dentate gyrus to enhance granule cell output

Joshua D Foster et al. Br J Pharmacol. 2013 Apr.

Abstract

Background and purpose: Activation of GABAB receptors in the dentate gyrus (DG) enhances granule cell (GC) activity by reducing synaptic inhibition imposed by hilar interneurons. This disinhibitory action facilitates signal transfer from the perforant path to the hippocampus. However, as the two main molecular subtypes, GABA(B(1a,2)) and GABA(B(1b,2)) receptors, prefer axonal terminal and dendritic compartments, respectively, they may modulate the hilar pathways at different synaptic localizations. We examined their relative expression and functions in the DG.

Experimental approach: The localization of GABAB subtypes was revealed immunohistochemically using subunit-selective antibodies in GABA(B1a)(-/-) and GABA(B1b)(-/-) mice. Effects of subtype activation by the GABAB receptor agonist, baclofen, were examined on the perforant path-stimulated GC population activities in brain slices.

Key results: GABA(B(1a,2)) receptors were concentrated in the inner molecular layer, the neuropil of the hilus and hilar neurons at the border zone; while GABA(B(1b,2)) receptors dominated the outer molecular layer and hilar neurons in the deep layer, showing their differential localization on GC dendrite and in the hilus. Baclofen enhanced the GC population spike to a larger extent in the GABA(B1b)(-/-) mice, demonstrating exclusively disinhibitory roles of the GABA(B(1a,2)) receptors. Conversely, in the GABA(B1a)(-/-) mice baclofen not only enhanced but also inhibited the population spike during GABAA blockade, revealing both disinhibitory and inhibitory effects of GABA(B(1b,2)) receptors.

Conclusions and implications: The GABA(B(1a,2)) and GABA(B(1b,2)) receptor subtypes differentially modulate GC outputs via selective axonal terminal and dendritic locations in the hilar pathways. The GABA(B(1a,2)) receptors exclusively mediate disinhibition, thereby playing a greater role in gating signal transfer for hippocampal spatial and pattern learning.

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Figures

Figure 1
Figure 1
Distribution of GABAB receptor subunits in the DG of 1a–/– and 1b–/– mice. (A–C) The Nissl stain in the DG shows no significant anatomical differences for cell populations in the GC layer, molecular layer (Mol) and the hilus (H) between the wild-type (WT), 1a–/– and 1b–/– mice. (D–F) GABAB1 immunolabelling in the DG using an immunoperoxidase method reveals high intensity staining in the cell bodies and proximal dendrites of hilar neurons, and in the neuropil of the inner molecular layer (IM, see panel G). The number of immunopositive hilar neurons is lowered in the 1a–/– (E) and 1b–/– mice (F). The neuropil staining is reduced in the IM in the 1a–/– mice and the outer molecular layer (OM, see panel G) in the 1b–/– mice. (G–I) GABAB2 immunoperoxidase labelling in the DG show that the relative neuropil staining intensities in the IM and the OM were reduced in the 1a–/– (H) and the 1b–/– mice (I) respectively. (J–L) Examples of negative control sections processed without the addition of GABAB1 or GABAB2 antibodies show low levels of background staining. The scale bar for all sections (200 μm) is shown in panel A. (M–R) Enlarged sections from panels D–I (see the frame in panel E) showing the immunostaining patterns in the molecular layer and hilar neurons.
Figure 2
Figure 2
Comparison of GABAB receptor subtype expression in the molecular layer (A–C) and hilar neurons (D–F). (A) The relative intensity scores of B1 immunostaining were significantly reduced in the IM in the 1a–/– mice (*) and in the OM only in the 1b–/– mice (*) compared with the WT. (B) The relative intensity scores of B2 immunostaining were significantly reduced in the IM in the 1a–/– (*) and the OM in the 1b–/– mice (*). The scores range from 0 (no staining) to 3 (the highest intensity) and were used for all sections the brain processed simultaneously. Each score was the mean from 8–20 sections. Nonparametric Kruskal–Wallis test and Dunn's post tests were performed. (C) A schematic of the relative co-localization of 1a, 1b and B2 subunits in the molecular layer. (D) The relative intensity scores of B2 immunostaining were significantly reduced in the hilus in the 1a–/– mice (*P < 0.05, nonparametric Kruskal–Wallis test and Dunn's post tests). (E) The total number of immunopositive hilar neurons (Total) was significantly decreased in the 1a–/– (***) and 1b–/– mice (***). The number of neurons at the hilus–GC border zone (Border) also significantly decreased in the 1a–/– (***) and 1b–/– mice (*). However, the number of hilar neurons in deep layers was only significantly lower in the 1b–/– mice (*). The data were mean counts from 8–20 sections per brain. Two-way anova and Bonferroni's multiple comparison tests were used (*P < 0.05, **P < 0.01, ***P < 0.001). N = 4 brains of each genotype. (F) Venn diagrams illustrate the relative percentages of hilar neurons containing 1a, 1b or both in the border zone and the deep layer respectively.
Figure 3
Figure 3
The GABAB receptor agonist, baclofen (Bac), enhances the PS in the DG. (A) A schematic of the multi-electrode positions in the DG for simultaneous recordings of the fEPSPs and the PSs. Electrical stimulation was applied to an electrode in the outer two-thirds of the molecular layer (Mol) and evoked fEPSPs were recorded in the outer molecular layer and PSs adjacent to the GC layer. (B) fEPSPs and PSs were simultaneously recorded at stimulation intensities ranging from 10 to 110 μA with a 10 μA incremental step. The PS amplitude and the fEPSP slope were normalized and plotted at all stimulation intensities. The relationships between the PS amplitude and the fEPSP slope are similar between the wild-type and the 1a–/– and 1b–/– mice (F[2224] = 0.917, P > 0.05), indicating unaltered coupling between the excitatory synaptic transmission and the GC excitability. (C–E) Bath application of 10 μM Bac significantly increased the PS areas in all genotypes (###P < 0.001, compared to baseline). The effects were rapidly reduced by CGP55845, showing GABAB receptor activation. F. Bac concentration-dependently increased the PS area in all mice (***F[3,71] = 84.6). At 10 μM, Bac induced a significantly larger effect in the 1b–/– mice compared with the wild-type (*) and 1a–/– mice (***). Bac also concentration-dependently increased the PS amplitude in all genotypes (G, ***F[3,71] = 17.6). (H and I) The fEPSP slopes were not altered by the application of Bac or CGP55845 in all genotypes (G, F[1,15] = 0.3, P > 0.05; I, F[3,71] = 2.1, P > 0.05). Repeated-measure two-way anova followed by Bonferroni post test was used for comparison (*P < 0.05, **P < 0.01 and ***P < 0.001).
Figure 4
Figure 4
The baclofen-induced enhancement of the PS is GABAA receptor-dependent. (A–C) The GABAA receptor antagonist, bicuculline (10 μM), induced multiple spikes in the PSs and significantly (***P < 0.001, compared with the baseline) increased the PS area, showing increased GC excitability. In the presence of bicuculline, baclofen (Bac) failed to increase the PS area because of the blockade of GABAA receptors. However, Bac significantly decreased the PS area in wild-type and 1a–/– mice (###P < 0.001, compared with bicuculline treatment), but not in 1b–/– mice, showing an inhibitory effect mediated by GABAB(1b,2) receptors. CGP55845 reduced the effect of Bac, confirming GABAB receptor activation. A comparison of Bac-induced inhibition between genotypes is shown in panel D (***P < 0.001, one-way anova followed by Tukey's test).
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