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GABA(B) Receptor Subtypes Differentially Modulate Synaptic Inhibition in the Dentate Gyrus to Enhance Granule Cell Output.

Foster, JD, Kitchen, I, Bettler, B and Chen, Y (2012) GABA(B) Receptor Subtypes Differentially Modulate Synaptic Inhibition in the Dentate Gyrus to Enhance Granule Cell Output. Br J Pharmacol, 168 (8). pp. 1808-1819.

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Abstract

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 localisations. We examined their relative expression and functions in the DG. EXPERIMENTAL APPROACH: The localisation 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 localisation 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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine > Department of Biochemical Sciences
Authors :
AuthorsEmailORCID
Foster, JDUNSPECIFIEDUNSPECIFIED
Kitchen, IUNSPECIFIEDUNSPECIFIED
Bettler, BUNSPECIFIEDUNSPECIFIED
Chen, YUNSPECIFIEDUNSPECIFIED
Date : 27 November 2012
Identification Number : 10.1111/bph.12073
Additional Information : This is the peer reviewed version of the following article: Foster JD, Kitchen I, Bettler B, Chen Y GABA(B) Receptor Subtypes Differentially Modulate Synaptic Inhibition in the Dentate Gyrus to Enhance Granule Cell Output. Br J Pharmacol 168 (8) pp 1808-1819, DOI: 10.1111/bph.12073which has been published in final form at http://dx.doi.org/10.1111/bph.12073. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Depositing User : Symplectic Elements
Date Deposited : 01 Jul 2015 15:55
Last Modified : 01 Jul 2015 15:55
URI: http://epubs.surrey.ac.uk/id/eprint/804208

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