GABAB receptor subtypes differentially modulate synaptic inhibition in the dentate gyrus to enhance granule cell output. (25th March 2013)

• Record Type: Journal Article
• Authors: Foster, Joshua D; Kitchen, Ian; Bettler, Bernhard; Chen, Ying
• Is Part Of: British journal of pharmacology. Volume 168:Number 8(2013:Apr.)
• Page Start: 1808
• Page End: 1819
• Publication Date: 2013-03-25
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12073
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12073-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>Activation of GABA<sub>B</sub> 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<sub>B</sub><sub>(1a, 2)</sub> and GABA<sub>B</sub><sub>(1b, 2)</sub> 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.</p> </sec> <sec id="bph12073-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>The localization of GABA<sub>B</sub> subtypes was revealed immunohistochemically using subunit‐selective antibodies in GABA<sub>B</sub><sub>1a</sub><sup>–/–</sup> and GABA<sub>B</sub><sub>1b</sub><sup>–/–</sup> mice. Effects of subtype activation by the GABA<sub>B</sub> receptor agonist, baclofen, were examined on the perforant path‐stimulated GC population activities in brain slices.</p> </sec> <sec id="bph12073-sec-0003" sec-type="section"> <title>Key Results</title> <p>GABA<sub>B</sub><sub>(1a, 2)</sub> receptors were concentrated in the inner molecular layer, the neuropil of the hilus and hilar neurons at the border zone; while GABA<sub>B</sub><sub>(1b, 2)</sub> 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<sub>B1b</sub><sup>–/–</sup> mice, demonstrating exclusively disinhibitory roles of the GABA<sub>B</sub><sub>(1a, 2)</sub> receptors. Conversely, in the GABA<sub>B1a</sub><sup>–/–</sup> mice baclofen not only enhanced but also inhibited the population spike during GABA<sub>A</sub> blockade, revealing both disinhibitory and inhibitory effects of GABA<sub>B</sub><sub>(1b, 2)</sub> receptors.</p> </sec> <sec id="bph12073-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>The GABA<sub>B</sub><sub>(1a, 2)</sub> and GABA<sub>B</sub><sub>(1b, 2)</sub> receptor subtypes differentially modulate GC outputs via selective axonal terminal and dendritic locations in the hilar pathways. The GABA<sub>B</sub><sub>(1a, 2)</sub> receptors exclusively mediate disinhibition, thereby playing a greater role in gating signal transfer for hippocampal spatial and pattern learning.</p> </sec> </abstract>