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

Joshua David Foster, Ian Kitchen, Bernhard Bettler, Ying Chen

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

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, GABAB(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 GABAB1b -/- 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 GABAB (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 GABAB1b -/- mice, demonstrating exclusively disinhibitory roles of the GABAB(1a,2) receptors. Conversely, in the GABAB1a -/- 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 GABAB(1a,2) and GABAB(1b,2) receptor subtypes differentially modulate GC outputs via selective axonal terminal and dendritic locations in the hilar pathways. The GABAB(1a,2) receptors exclusively mediate disinhibition, thereby playing a greater role in gating signal transfer for hippocampal spatial and pattern learning.
Original languageEnglish
Pages (from-to)1808-1819
JournalBritish Journal of Pharmacology
Volume168
Issue number8
Early online date25 Mar 2013
DOIs
Publication statusPublished - 1 Apr 2013

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