Universität zu Köln

Jacob, Tija C., Michels, Guido, Silayeva, Liliya, Haydon, Julia, Succol, Francesca and Moss, Stephen J. (2012). Benzodiazepine treatment induces subtype-specific changes in GABA(A) receptor trafficking and decreases synaptic inhibition. Proc. Natl. Acad. Sci. U. S. A., 109 (45). S. 18595 - 18601. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

Benzodiazepines potentiate gamma-aminobutyric acid type A receptor (GABA(A)R) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The mechanisms leading to BZ tolerance are unknown. BZs bind at the interface between an a and gamma subunit of GABA(A)Rs, preferentially enhancing synaptic receptors largely composed of alpha(1-3, 5), beta 3, and gamma 2 subunits. Using confocal imaging and patch-clamp approaches, we show that treatment with the BZ flurazepam decreases GABA(A)R surface levels and the efficacy of neuronal inhibition in hippocampal neurons. A dramatic decrease in surface and total levels of alpha 2 subunit-containing GABA(A)Rs occurred within 24 h of flurazepam treatment, whereas GABA(A)Rs incorporating alpha 1 subunits showed little alteration. The GABA(A)R surface depletion could be reversed by treatment with the BZ antagonist Ro 15-1788. Coincident with decreased GABA(A)R surface levels, flurazepamtreatment reduced miniature inhibitory postsynaptic current amplitude, which returned to control levels with acute Ro 15-1788 treatment. GABA(A)R endocytosis and insertion rates were unchanged by flurazepam treatment. Treatment with leupeptin restored flurazepam lowered receptor surface levels, strongly suggesting that flurazepam increases lysosomal degradation of GABA(A)Rs. Together, these data suggest that flurazepam exposure enhances degradation of alpha 2 subunit-containing GABA(A)Rs after their removal from the plasma membrane, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition. These reported subtype-specific changes in GABA(A)R trafficking provide significant mechanistic insight into the initial neuroadaptive responses occurring with BZ treatment.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Jacob, Tija C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Michels, Guido UNSPECIFIED UNSPECIFIED UNSPECIFIED Silayeva, Liliya UNSPECIFIED UNSPECIFIED UNSPECIFIED Haydon, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Succol, Francesca UNSPECIFIED UNSPECIFIED UNSPECIFIED Moss, Stephen J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-479098
DOI:	10.1073/pnas.1204994109
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	109
Number:	45
Page Range:	S. 18595 - 18601
Date:	2012
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language AMINOBUTYRIC ACID(A) RECEPTORS; A-RECEPTOR; MEMBRANE TRAFFICKING; HIPPOCAMPAL-NEURONS; GABAERGIC SYNAPSES; DIRECT BINDING; MODULATION; TOLERANCE; DIAZEPAM; CELLS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47909