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Auferkorte O.N.,Max Planck Institute for Brain Research | Baden T.,University of Tubingen | Kaushalya S.K.,Max Planck Institute for Medical Research | Zabouri N.,Max Planck Institute for Brain Research | And 4 more authors.
PLoS ONE | Year: 2012

Far from being a simple sensor, the retina actively participates in processing visual signals. One of the best understood aspects of this processing is the detection of motion direction. Direction-selective (DS) retinal circuits include several subtypes of ganglion cells (GCs) and inhibitory interneurons, such as starburst amacrine cells (SACs). Recent studies demonstrated a surprising complexity in the arrangement of synapses in the DS circuit, i.e. between SACs and DS ganglion cells. Thus, to fully understand retinal DS mechanisms, detailed knowledge of all synaptic elements involved, particularly the nature and localization of neurotransmitter receptors, is needed. Since inhibition from SACs onto DSGCs is crucial for generating retinal direction selectivity, we investigate here the nature of the GABA receptors mediating this interaction. We found that in the inner plexiform layer (IPL) of mouse and rabbit retina, GABA A receptor subunit α2 (GABA AR α2) aggregated in synaptic clusters along two bands overlapping the dendritic plexuses of both ON and OFF SACs. On distal dendrites of individually labeled SACs in rabbit, GABA AR α2 was aligned with the majority of varicosities, the cell's output structures, and found postsynaptically on DSGC dendrites, both in the ON and OFF portion of the IPL. In GABA AR α2 knock-out (KO) mice, light responses of retinal GCs recorded with two-photon calcium imaging revealed a significant impairment of DS responses compared to their wild-type littermates. We observed a dramatic drop in the proportion of cells exhibiting DS phenotype in both the ON and ON-OFF populations, which strongly supports our anatomical findings that α2-containing GABA ARs are critical for mediating retinal DS inhibition. Our study reveals for the first time, to the best of our knowledge, the precise functional localization of a specific receptor subunit in the retinal DS circuit. © 2012 Auferkorte et al.

Martin C.B.P.,University of Paris Descartes | Martin C.B.P.,University Pierre and Marie Curie | Martin C.B.P.,French Institute of Health and Medical Research | Gassmann M.,University of Basel | And 14 more authors.
Journal of Neurochemistry | Year: 2014

Serotonin (5-HT)2C receptors play a role in psychoaffective disorders and often contribute to the antidepressant and anxiolytic effects of psychotropic drugs. During stress, activation of these receptors exerts a negative feedback on 5-HT release, probably by increasing the activity of GABAergic interneurons. However, to date, the GABA receptor types that mediate the 5-HT2C receptor-induced feedback inhibition are still unknown. To address this question, we assessed the inhibition of 5-HT turnover by a 5-HT2C receptor agonist (RO 60-0175) at the hippocampal level and under conditions of stress, after pharmacological or genetic inactivation of either GABA-A or GABA-B receptors in mice. Neither the GABA-B receptor antagonist phaclofen nor the specific genetic ablation of either GABA-B1a or GABA-B1b subunits altered the inhibitory effect of RO 60-0175, although 5-HT turnover was markedly decreased in GABA-B1a knock-out mice in both basal and stress conditions. In contrast, the 5-HT2C receptormediated inhibition of 5-HT turnover was reduced by the GABA-A receptor antagonist bicuculline. However, a significant effect of 5-HT2C receptor activation persisted in mutant mice deficient in the α3 subunit of GABA-A receptors. It can be inferred that non-α3 subunit-containing GABA-A receptors, but not GABA-B receptors, mediate the 5-HT2C-induced inhibition of stress-induced increase in hippocampal 5-HT turnover in mice. © 2014 International Society for Neurochemistry.

Antkowiak B.,University of Tubingen | Rudolph U.,Laboratory of Genetic Neuropharmacology | Rudolph U.,Harvard University
Current Opinion in Anaesthesiology | Year: 2016

Purpose of review The review highlights novel insights into the role of γ-aminobutyric acid A (GABA A) receptors in mediating clinically relevant actions of anesthetic agents. Recent findings GABA A receptors in the hippocampus are located on glutamatergic pyramidal cells and GABAergic interneurons. Etomidate-induced inhibition of a synaptic correlate of learning and memory is caused by receptors on nonpyramidal neurons, likely on interneurons that incorporate α5 subunits. Selective enhancement of α2 subunit containing GABA A receptors in the spinal cord provides antihyperalgesia against inflammatory and neuropathic pain without causing sedation, motor impairment, and tolerance development. Inflammation, traumatic brain injury, and exposure to anesthetic agents modify the expression patterns of GABA A receptors in a subtype-specific manner. These modifications may persist for weeks. The neuroactive steroid alphaxalone causes fast-onset and short-duration anesthesia in humans. Cardiovascular and respiratory side-effects are less severe than with propofol. Summary Identification of the molecular and cellular substrates involved in anesthesia and insights into disease and drug-induced alterations in the expression patterns of GABA A receptors in the central nervous system are emphasizing the need for individualized anesthesia care. Introducing neuroactive steroids into clinical anesthesia is expected to reduce cardiovascular and respiratory side-effects. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Crestani F.,University of Zurich | Rudolph U.,Laboratory of Genetic Neuropharmacology | Rudolph U.,Harvard University
Advances in Pharmacology | Year: 2015

GABAA receptors are the major inhibitory neurotransmitter receptors in the brain. They are heteropentamers that are typically classified according to their α subunits. By rendering each of the benzodiazepine-sensitive α subunits (α1, α2, α3, and α5) insensitive to modulation by classical benzodiazepines by His to Arg point mutations in knock-in mice, we were able to identify behavioral functions mediated by different GABAA receptor subtypes, which led to the development of novel therapeutic strategies. In this chapter, we provide a largely chronological overview on behavioral studies on GABAA receptor mutant mice at the Institute of Pharmacology and Toxicology at the University of Zurich. © 2015 Elsevier Inc.

Ralvenius W.T.,University of Zurich | Ralvenius W.T.,Center for Neuroscience Zurich | Benke D.,University of Zurich | Benke D.,Center for Neuroscience Zurich | And 7 more authors.
Nature Communications | Year: 2015

Agonists at the benzodiazepine-binding site of GABAA receptors (BDZs) enhance synaptic inhibition through four subtypes (α1, α2, α3 and α5) of GABAA receptors (GABAA R). When applied to the spinal cord, they alleviate pathological pain; however, insufficient efficacy after systemic administration and undesired effects preclude their use in routine pain therapy. Previous work suggested that subtype-selective drugs might allow separating desired antihyperalgesia from unwanted effects, but the lack of selective agents has hitherto prevented systematic analyses. Here we use four lines of triple GABAA R point-mutated mice, which express only one benzodiazepine-sensitive GABAA R subtype at a time, to show that targeting only α2GABAA Rs achieves strong antihyperalgesia and reduced side effects (that is, no sedation, motor impairment and tolerance development). Additional pharmacokinetic and pharmacodynamic analyses in these mice explain why clinically relevant antihyperalgesia cannot be achieved with nonselective BDZs. These findings should foster the development of innovative subtype-selective BDZs for novel indications such as chronic pain. © 2015 Macmillan Publishers Limited. All rights reserved.

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