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

Background and Purpose

Activation of GABA_B 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 GABA_B subtypes was revealed immunohistochemically using subunit‐selective antibodies in GABA_B1a^–/– and GABA_B1b^–/– mice. Effects of subtype activation by the GABA_B 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 GABA_A 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.

DOI: 10.1111/bph.12073

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