Publications by authors named "Bernhard Bettler"

134 Publications

GABA receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals.

Elife 2021 Apr 29;10. Epub 2021 Apr 29.

Neuroscience, Institute of Science and Technology Austria, Klosterneuburg, Austria.

The synaptic connection from medial habenula (MHb) to interpeduncular nucleus (IPN) is critical for emotion-related behaviors, and uniquely expresses R-type Ca channels (Cav2.3) and auxiliary GABA receptor (GBR) subunits, the K-channel tetramerization domain-containing proteins (KCTDs). Activation of GBRs facilitates or inhibits transmitter release from MHb terminals depending on the IPN subnucleus, but the role of KCTDs is unknown. We therefore examined the localization and function of Cav2.3, GBRs, and KCTDs in this pathway in mice. We show in heterologous cells that KCTD8 and KCTD12b directly bind to Cav2.3 and that KCTD8 potentiates Cav2.3 currents in the absence of GBRs. In the rostral IPN, KCTD8, KCTD12b and Cav2.3 co-localize at the presynaptic active zone. Genetic deletion indicated a bidirectional modulation of Cav2.3-mediated release by these KCTDs with a compensatory increase of KCTD8 in the active zone in KCTD12b-deficient mice. The interaction of Cav2.3 with KCTDs therefore scales synaptic strength independent of GBR activation.
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http://dx.doi.org/10.7554/eLife.68274DOI Listing
April 2021

COR758, a negative allosteric modulator of GABA receptors.

Neuropharmacology 2021 Mar 30;189:108537. Epub 2021 Mar 30.

Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, Italy; Guy Everett Laboratory, University of Cagliari, 09042, Monserrato, Italy; Center of Excellence "Neurobiology of Addiction", University of Cagliari, 09042, Monserrato, Italy. Electronic address:

Allosteric modulators of G protein coupled receptors (GPCRs), including GABARs (GABARs), are promising therapeutic candidates. While several positive allosteric modulators (PAM) of GABARs have been characterized, only recently the first negative allosteric modulator (NAM) has been described. In the present study, we report the characterization of COR758, which acts as GABAR NAM in rat cortical membranes and CHO cells stably expressing GABARs (CHO-GABA). COR758 failed to displace the antagonist [H]CGP54626 from the orthosteric binding site of GABARs showing that it acts through an allosteric binding site. Docking studies revealed a possible new allosteric binding site for COR758 in the intrahelical pocket of the GABA monomer. COR758 inhibited basal and GABAR-stimulated O-(3-[Sthio)-triphosphate ([S]GTPγS) binding in brain membranes and blocked the enhancement of GABAR-stimulated [S]GTPγS binding by the PAM GS39783. Bioluminescent resonance energy transfer (BRET) measurements in CHO-GABA cells showed that COR758 inhibited G protein activation by GABA and altered GABAR subunit rearrangements. Additionally, the compound altered GABAR-mediated signaling such as baclofen-induced inhibition of cAMP production in transfected HEK293 cells, agonist-induced Ca mobilization as well as baclofen and the ago-PAM CGP7930 induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in CHO-GABA cells. COR758 also prevented baclofen-induced outward currents recorded from rat dopamine neurons, substantiating its property as a NAM for GABARs. Altogether, these data indicate that COR758 inhibits G protein signaling by GABARs, likely by interacting with an allosteric binding-site. Therefore, COR758 might serve as a scaffold to develop additional NAMs for therapeutic intervention.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108537DOI Listing
March 2021

Symmetric signal transduction and negative allosteric modulation of heterodimeric mGlu1/5 receptors.

Neuropharmacology 2020 Dec 3;190:108426. Epub 2020 Dec 3.

Department of Biomedicine, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland. Electronic address:

For a long time metabotropic glutamate receptors (mGluRs) were thought to regulate neuronal functions as obligatory homodimers. Recent reports, however, indicate the existence of heterodimers between group-II and -III mGluRs in the brain, which differ from the homodimers in their signal transduction and sensitivity to negative allosteric modulators (NAMs). Whether the group-I mGluRs, mGlu1 and mGlu5, form functional heterodimers in the brain is still a matter of debate. We now show that mGlu1 and mGlu5 co-purify from brain membranes and hippocampal tissue and co-localize in cultured hippocampal neurons. Complementation assays with mutants deficient in agonist-binding or G protein-coupling reveal that mGlu1/5 heterodimers are functional in heterologous cells and transfected cultured hippocampal neurons. In contrast to heterodimers between group-II and -III mGluRs, mGlu1/5 receptors exhibit a symmetric signal transduction, with both protomers activating G proteins to a similar extent. NAMs of either protomer in mGlu1/5 receptors partially inhibit signaling, showing that both protomers need to be able to reach an active conformation for full receptor activity. Complete heterodimer inhibition is observed when both protomers are locked in their inactive state by a NAM. In summary, our data show that mGlu1/5 heterodimers exhibit a symmetric signal transduction and thus intermediate signaling efficacy and kinetic properties. Our data support the existence of mGlu1/5 heterodimers in neurons and highlight differences in the signaling transduction of heterodimeric mGluRs that influence allosteric modulation.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108426DOI Listing
December 2020

Targeting receptor complexes: a new dimension in drug discovery.

Nat Rev Drug Discov 2020 12 11;19(12):884-901. Epub 2020 Nov 11.

Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.

Targeting receptor proteins, such as ligand-gated ion channels and G protein-coupled receptors, has directly enabled the discovery of most drugs developed to modulate receptor signalling. However, as the search for novel and improved drugs continues, an innovative approach - targeting receptor complexes - is emerging. Receptor complexes are composed of core receptor proteins and receptor-associated proteins, which have profound effects on the overall receptor structure, function and localization. Hence, targeting key protein-protein interactions within receptor complexes provides an opportunity to develop more selective drugs with fewer side effects. In this Review, we discuss our current understanding of ligand-gated ion channel and G protein-coupled receptor complexes and discuss strategies for their pharmacological modulation. Although such strategies are still in preclinical development for most receptor complexes, they exemplify how receptor complexes can be drugged, and lay the groundwork for this nascent area of research.
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http://dx.doi.org/10.1038/s41573-020-0086-4DOI Listing
December 2020

Structural Basis of GABA Receptor Regulation and Signaling.

Curr Top Behav Neurosci 2020 Aug 19. Epub 2020 Aug 19.

Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Basel, Switzerland.

GABA receptors (GBRs), the G protein-coupled receptors for the inhibitory neurotransmitter γ-aminobutyric acid (GABA), activate Go/i-type G proteins that regulate adenylyl cyclase, Ca channels, and K channels. GBR signaling to enzymes and ion channels influences neuronal activity, plasticity processes, and network activity throughout the brain. GBRs are obligatory heterodimers composed of GB1a or GB1b subunits with a GB2 subunit. Heterodimeric GB1a/2 and GB1b/2 receptors represent functional units that associate in a modular fashion with regulatory, trafficking, and effector proteins to generate receptors with distinct physiological functions. This review summarizes current knowledge on the structure, organization, and functions of multi-protein GBR complexes.
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http://dx.doi.org/10.1007/7854_2020_147DOI Listing
August 2020

Reduction in the neuronal surface of post and presynaptic GABA receptors in the hippocampus in a mouse model of Alzheimer's disease.

Brain Pathol 2020 05 12;30(3):554-575. Epub 2019 Dec 12.

Synaptic Structure Laboratory, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Campus Biosanitario, C/ Almansa 14, 02008, Albacete, Spain.

The hippocampus plays key roles in learning and memory and is a main target of Alzheimer's disease (AD), which causes progressive memory impairments. Despite numerous investigations about the processes required for the normal hippocampal functions, the neurotransmitter receptors involved in the synaptic deficits by which AD disables the hippocampus are not yet characterized. By combining histoblots, western blots, immunohistochemistry and high-resolution immunoelectron microscopic methods for GABA receptors, this study provides a quantitative description of the expression and the subcellular localization of GABA in the hippocampus in a mouse model of AD at 1, 6 and 12 months of age. Western blots and histoblots showed that the total amount of protein and the laminar expression pattern of GABA were similar in APP/PS1 mice and in age-matched wild-type mice. In contrast, immunoelectron microscopic techniques showed that the subcellular localization of GABA subunit did not change significantly in APP/PS1 mice at 1 month of age, was significantly reduced in the stratum lacunosum-moleculare of CA1 pyramidal cells at 6 months of age and significantly reduced at the membrane surface of CA1 pyramidal cells at 12 months of age. This reduction of plasma membrane GABA was paralleled by a significant increase of the subunit at the intracellular sites. We further observed a decrease of membrane-targeted GABA receptors in axon terminals contacting CA1 pyramidal cells. Our data demonstrate compartment- and age-dependent reduction of plasma membrane-targeted GABA receptors in the CA1 region of the hippocampus, suggesting that this decrease might be enough to alter the GABA -mediated synaptic transmission taking place in AD.
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http://dx.doi.org/10.1111/bpa.12802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317930PMC
May 2020

GABA Receptor Signaling in the Mesolimbic System Suppresses Binge-like Consumption of a High-Fat Diet.

iScience 2019 Oct 26;20:337-347. Epub 2019 Sep 26.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan. Electronic address:

Binge eating could contribute to the development of obesity, and previous studies suggest that gamma-aminobutyric acid (GABA) type B receptor (GABAR) signaling is involved in the regulation of binge eating. Here, we show that time-restricted access to a high-fat diet (HFD) induces binge-like eating behavior in wild-type mice. HFD consumption during restricted time was significantly increased in corticostriatal neuron-specific GABAR-deficient mice compared with wild-type mice. Furthermore, the GABAR agonist baclofen suppressed HFD intake during restricted time in wild-type mice but not in corticostriatal or dopaminergic neuron-specific GABAR-deficient mice. In contrast, there were no significant differences in food consumption among genotypes under ad libitum access to HFD. Thus, our data show that the mesolimbic system regulates food consumption under time-restricted but not ad libitum access to HFD and have identified a mechanism by which GABAR signaling suppresses binge-like eating of HFD.
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http://dx.doi.org/10.1016/j.isci.2019.09.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817655PMC
October 2019

Pianp deficiency links GABA receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior.

Mol Psychiatry 2020 11 11;25(11):2979-2993. Epub 2019 Sep 11.

Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany.

Pianp (also known as Leda-1) is a type I transmembrane protein with preferential expression in the mammalian CNS. Its processing is characterized by proteolytic cleavage by a range of proteases including Adam10, Adam17, MMPs, and the γ-secretase complex. Pianp can interact with Pilrα and the GB1a subunit of the GABA receptor (GBR) complex. A recent case description of a boy with global developmental delay and homozygous nonsense variant in PIANP supports the hypothesis that PIANP is involved in the control of behavioral traits in mammals. To investigate the physiological functions of Pianp, constitutive, global knockout mice were generated and comprehensively analyzed. Broad assessment did not indicate malformation or malfunction of internal organs. In the brain, however, decreased sizes and altered cellular compositions of the dentate gyrus as well as the cerebellum, including a lower number of cerebellar Purkinje cells, were identified. Functionally, loss of Pianp led to impaired presynaptic GBR-mediated inhibition of glutamate release and altered gene expression in the cortex, hippocampus, amygdala, and hypothalamus including downregulation of Erdr1, a gene linked to autism-like behavior. Behavioral phenotyping revealed that Pianp deficiency leads to context-dependent enhanced anxiety and spatial learning deficits, an altered stress response, severely impaired social interaction, and enhanced repetitive behavior, which all represent characteristic features of an autism spectrum disorder-like phenotype. Altogether, Pianp represents a novel candidate gene involved in autism-like behavior, cerebellar and hippocampal pathology, and GBR signaling.
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http://dx.doi.org/10.1038/s41380-019-0519-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577901PMC
November 2020

Targeting the γ-Aminobutyric Acid Type B (GABA) Receptor Complex: Development of Inhibitors Targeting the K Channel Tetramerization Domain (KCTD) Containing Proteins/GABA Receptor Protein-Protein Interaction.

J Med Chem 2019 10 25;62(19):8819-8830. Epub 2019 Sep 25.

Center for Biopharmaceuticals, Department of Drug Design and Pharmacology , University of Copenhagen , 2100 Copenhagen , Denmark.

Targeting multiprotein receptor complexes, rather than receptors directly, is a promising concept in drug discovery. This is particularly relevant to the GABA receptor complex, which plays a prominent role in many brain functions and diseases. Here, we provide the first studies targeting a key protein-protein interaction of the GABA receptor complex-the interaction with KCTD proteins. By employing the μSPOT technology, we first defined the GABA receptor-binding epitope mediating the KCTD interaction. Subsequently, we developed a highly potent peptide-based inhibitor that interferes with the KCTD/GABA receptor complex and efficiently isolates endogenous KCTD proteins from mouse brain lysates. X-ray crystallography and SEC-MALS revealed inhibitor induced oligomerization of KCTD16 into a distinct hexameric structure. Thus, we provide a template for modulating the GABA receptor complex, revealing a fundamentally novel approach for targeting GABA receptor-associated neuropsychiatric disorders.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01087DOI Listing
October 2019

Multiple failures in the lutenising hormone surge generating system in GABAB1KO female mice.

J Neuroendocrinol 2019 08 15;31(8):e12765. Epub 2019 Jul 15.

Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.

Female mice lacking GABAB receptors, GABAB1KO, show disrupted oestrous cycles, reduced pregnancies and increased hypothalamic Gnrh1 mRNA expression, whereas anteroventral periventricular/periventricular preoptic nucleus (AVPV/PeN) Kiss1 mRNA was not affected. In the present study, we characterise the important components of the gonadotrophic preovulatory surge, aiming to unravel the origin of this reproductive impairment. In GABAB1KO and wild-type (WT) females, we determined: (i) hypothalamic oestrogen receptor (ER)α and β and aromatase mRNA and protein expression; (ii) ovulation index and oestrus serum follicle-stimulating hormone (FSH) and pituitary Gnrh1r expression; (iii) in ovariectomised-oestradiol valerate-treated mice, we evaluated ex vivo hypothalamic gonadotrophin-releasing hormone (GnRH) pulsatility in the presence/absence of kisspeptin (Kiss-10, constant or pulsatile) and oestradiol (constant); and (iv) in ovariectomised-oestradiol silastic capsule-treated mice (proestrous-like environment), we evaluated morning and evening kisspeptin neurone activation (c-Fos+) and serum luteinising homrone (LH). In the medial basal hypothalamus of oestrus GABAB1KOs, aromatase and ERα mRNA and protein were increased, whereas ERβ was decreased. In GABAB1KOs, the ovulation index was decreased together with decreased first oestrus serum FSH and increased pituitary Gnrh1r mRNA. Under constant Kiss-10 stimulation, hypothalamic GnRH pulse frequency did not vary, although GnRH mass/pulse was increased in GABAB1KOs. In WTs, pulsatile Kiss-10 together with constant oestradiol significantly increased GnRH pulsatility, whereas, in GABAB1KOs, oestradiol alone increased GnRH pulsatility and this was reversed by pulsatile Kiss-10 addition. In GABAB1KOs AVPV/PeN kisspeptin neurones were similarly activated (c-Fos+) in the morning and evening, whereas WTs showed the expected, marked evening stimulation. LH correlated with activated kisspeptin cells in WT mice, whereas GABAB1KO mice showed high, similar LH levels both in the morning and evening. Taken together, all of these alterations point to impairment in the trigger of the preovulatory GnRH surge that entails the reproductive alterations described.
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http://dx.doi.org/10.1111/jne.12765DOI Listing
August 2019

The organizing principle of GABA receptor complexes: Physiological and pharmacological implications.

Basic Clin Pharmacol Toxicol 2020 Jun 15;126 Suppl 6:25-34. Epub 2019 May 15.

Department of Biomedicine, Institute of Physiology, University of Basel, Basel, Switzerland.

GABA receptors (GBRs), the G protein-coupled receptors for the neurotransmitter γ-aminobutyric acid (GABA), regulate synaptic transmission at most synapses in the brain. Proteomic approaches revealed that native GBR complexes assemble from an inventory of ~30 proteins that provide a molecular basis for the functional diversity observed with these receptors. Studies with reconstituted GBR complexes in heterologous cells and complementary knockout studies have allowed to identify cellular and physiological functions for obligate and several non-obligate receptor components. It emerges that modular association of receptor components in space and time generates a variety of multiprotein receptor complexes with different localizations, kinetic properties and effector channels. This article summarizes current knowledge on the organizing principle of GBR complexes. We further discuss unanticipated receptor functions, links to disease and opportunities for drug discovery arising from the identification of novel receptor components.
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http://dx.doi.org/10.1111/bcpt.13241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317483PMC
June 2020

Complex formation of APP with GABA receptors links axonal trafficking to amyloidogenic processing.

Nat Commun 2019 03 22;10(1):1331. Epub 2019 Mar 22.

Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.

GABA receptors (GBRs) are key regulators of synaptic release but little is known about trafficking mechanisms that control their presynaptic abundance. We now show that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs. Of the three interacting proteins, selectively the genetic loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression. Proteomic and functional analyses revealed that APP associates with JIP and calsyntenin proteins that link the APP/GBR complex in cargo vesicles to the axonal trafficking motor. Complex formation with GBRs stabilizes APP at the cell surface and reduces proteolysis of APP to Aβ, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to Aβ formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases Aβ formation.
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http://dx.doi.org/10.1038/s41467-019-09164-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430795PMC
March 2019

GABA receptors modulate morphine antinociception: Pharmacological and genetic approaches.

Pharmacol Biochem Behav 2019 05 6;180:11-21. Epub 2019 Mar 6.

CONICET - Universidad de Buenos Aires, Instituto de Investigaciones Farmacológicas (ININFA), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Farmacología, Buenos Aires, Argentina. Electronic address:

Previous studies in our laboratory showed an interaction between the GABAergic and opioid systems involved in the analgesic effect of baclofen (BAC). Furthermore, it is known that sex differences exist regarding various pharmacological responses of morphine (MOR) and they are related to an increased sensitivity to MOR effects in males. The aims of the present study were to evaluate the possible involvement of the GABA receptors in the antinociceptive responses induced by MOR (1, 3 and 9 mg/kg, s.c.) administration using both pharmacological (BAC 2 mg/kg, i.p.; and 2-OH-saclofen, SAC 0.3 mg/kg, intra cisterna magna) and genetic approaches (GABA knockout mice; GABA KO) in mice of both sexes. In addition, we explored the alterations in c-Fos expression of different brain areas involved in the antinociceptive effect of MOR using both approaches. The pharmacological approach showed a higher dose-dependent antinociceptive effect of MOR in male mice compared to female mice. BAC and SAC pretreatment potentiated and attenuated the antinociceptive effect of MOR, respectively, in both sexes. The genetic approach revealed a dose-dependent antinociceptive effect of MOR in the wild type mice, but not in the GABA KO mice and no sex differences were observed. Additionally, BAC and SAC pretreatment and the lack of GABA subunit of the GABA receptor prevented the changes observed in c-Fos expression in the cingulate cortex and nucleus accumbens of male mice. Our results suggest that the GABA receptors are involved in the MOR antinociceptive effect of both male and female mice.
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http://dx.doi.org/10.1016/j.pbb.2019.02.015DOI Listing
May 2019

Constitutive activation of Notch2 signalling confers chemoresistance to neural stem cells via transactivation of fibroblast growth factor receptor-1.

Stem Cell Res 2019 03 7;35:101390. Epub 2019 Feb 7.

Department of Biomedicine, Pharmazentrum, University of Basel, 4056 Basel, Switzerland. Electronic address:

Notch signalling regulates neural stem cell (NSC) proliferation, differentiation and survival for the correct development and functioning of the central nervous system. Overactive Notch2 signalling has been associated with poor prognosis of aggressive brain tumours, such as glioblastoma multiforme (GBM). We recently reported that constitutive expression of the Notch2 intracellular domain (N2ICD) enhances proliferation and gliogenesis in NSCs. Here, we investigated the mechanism by which Notch2 promotes resistance to apoptosis of NSCs to cytotoxic insults. We performed ex vivo studies using NSC cultures from transgenic mice constitutively expressing N2ICD. These NSCs expressed increased levels of pro-survival factors and lack an apoptotic response to the topoisomerase inhibitor etoposide, not showing neither mitochondrial damage nor caspase activation. Interestingly, Notch2 signalling also regulated chemoresistance of human GBM cells to etoposide. We also identified a signalling crosstalk with FGF signalling pathway involved in this resistance to apoptosis of NSCs. Aberrant Notch2 expression enhances fibroblast growth factor receptor-1 (FGFR1) activity to specifically target the AKT-GSK3 signalling pathway to block apoptosis. These results have implications for understanding molecular changes involved in both tumorigenesis and therapy resistance.
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http://dx.doi.org/10.1016/j.scr.2019.101390DOI Listing
March 2019

Parvalbumin-Interneuron Output Synapses Show Spike-Timing-Dependent Plasticity that Contributes to Auditory Map Remodeling.

Neuron 2018 08 2;99(4):720-735.e6. Epub 2018 Aug 2.

Laboratory of Synaptic Mechanisms, Brain Mind Institute, School of Life Science, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address:

Parvalbumin (PV)-expressing interneurons mediate fast inhibition of principal neurons in many brain areas; however, long-term plasticity at PV-interneuron output synapses has been less well studied. In the auditory cortex, thalamic inputs drive reliably timed action potentials (APs) in principal neurons and PV-interneurons. Using paired recordings in the input layer of the mouse auditory cortex, we found a marked spike-timing-dependent plasticity (STDP) at PV-interneuron output synapses. Long-term potentiation of inhibition (iLTP) is observed upon postsynaptic (principal neuron) then presynaptic (PV-interneuron) AP firing. The opposite AP order causes GABA-mediated long-term depression of inhibition (iLTD), which is developmentally converted to iLTP in an experience-dependent manner. Genetic deletion of GABA receptors in principal neurons suppressed iLTD and produced deficits in auditory map remodeling. Output synapses of PV-interneurons thus show marked STDP, and one limb of this plasticity, GABA-dependent iLTD, is a candidate mechanism for disinhibition during auditory critical period plasticity.
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http://dx.doi.org/10.1016/j.neuron.2018.07.018DOI Listing
August 2018

A tribute to Norman G Bowery.

Neuropharmacology 2018 07 18;136(Pt A):1-2. Epub 2018 May 18.

University of Kansas Medical Center, United States. Electronic address:

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http://dx.doi.org/10.1016/j.neuropharm.2018.05.022DOI Listing
July 2018

Rimonabant, a potent CB1 cannabinoid receptor antagonist, is a Gα protein inhibitor.

Neuropharmacology 2018 05;133:107-120

Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, Italy; Center of Excellence "Neurobiology of Addiction", University of Cagliari, 09042, Monserrato, Italy. Electronic address:

Rimonabant is a potent and selective cannabinoid CB1 receptor antagonist widely used in animal and clinical studies. Besides its antagonistic properties, numerous studies have shown that, at micromolar concentrations rimonabant behaves as an inverse agonist at CB1 receptors. The mechanism underpinning this activity is unclear. Here we show that micromolar concentrations of rimonabant inhibited Gα-type G proteins, resulting in a receptor-independent block of G protein signaling. Accordingly, rimonabant decreased basal and agonist stimulated [S]GTPγS binding to cortical membranes of CB1- and GABA-receptor KO mice and Chinese Hamster Ovary (CHO) cell membranes stably transfected with GABA or D2 dopamine receptors. The structural analog of rimonabant, AM251, decreased basal and baclofen-stimulated GTPγS binding to rat cortical and CHO cell membranes expressing GABA receptors. Rimonabant prevented G protein-mediated GABA and D2 dopamine receptor signaling to adenylyl cyclase in Human Embryonic Kidney 293 cells and to G protein-coupled inwardly rectifying K channels (GIRK) in midbrain dopamine neurons of CB1 KO mice. Rimonabant suppressed GIRK gating induced by GTPγS in CHO cells transfected with GIRK, consistent with a receptor-independent action. Bioluminescent resonance energy transfer (BRET) measurements in living CHO cells showed that, in presence or absence of co-expressed GABA receptors, rimonabant stabilized the heterotrimeric Gαi/o-protein complex and prevented conformational rearrangements induced by GABA receptor activation. Rimonabant failed to inhibit Gαs-mediated signaling, supporting its specificity for Gα-type G proteins. The inhibition of Gα protein provides a new site of rimonabant action that may help to understand its pharmacological and toxicological effects occurring at high concentrations.
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http://dx.doi.org/10.1016/j.neuropharm.2018.01.024DOI Listing
May 2018

Interneuron-specific signaling evokes distinctive somatostatin-mediated responses in adult cortical astrocytes.

Nat Commun 2018 01 8;9(1):82. Epub 2018 Jan 8.

Neuroscience Institute, National Research Council (CNR), 35121, Padova, Italy.

The signaling diversity of GABAergic interneurons to post-synaptic neurons is crucial to generate the functional heterogeneity that characterizes brain circuits. Whether this diversity applies to other brain cells, such as the glial cells astrocytes, remains unexplored. Using optogenetics and two-photon functional imaging in the adult mouse neocortex, we here reveal that parvalbumin- and somatostatin-expressing interneurons, two key interneuron classes in the brain, differentially signal to astrocytes inducing weak and robust GABA receptor-mediated Ca elevations, respectively. Furthermore, the astrocyte response depresses upon parvalbumin interneuron repetitive stimulations and potentiates upon somatostatin interneuron repetitive stimulations, revealing a distinguished astrocyte plasticity. Remarkably, the potentiated response crucially depends on the neuropeptide somatostatin, released by somatostatin interneurons, which activates somatostatin receptors at astrocytic processes. Our study unveils, in the living brain, a hitherto unidentified signaling specificity between interneuron subtypes and astrocytes opening a new perspective into the role of astrocytes as non-neuronal components of inhibitory circuits.
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http://dx.doi.org/10.1038/s41467-017-02642-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758790PMC
January 2018

Differential association of GABA receptors with their effector ion channels in Purkinje cells.

Brain Struct Funct 2018 Apr 25;223(3):1565-1587. Epub 2017 Nov 25.

Department of Histological and Physiological Sciences, Faculty of Medical Science, University of Fukui, Yoshida, Fukui, 910-1193, Japan.

Metabotropic GABA receptors mediate slow inhibitory effects presynaptically and postsynaptically through the modulation of different effector signalling pathways. Here, we analysed the distribution of GABA receptors using highly sensitive SDS-digested freeze-fracture replica labelling in mouse cerebellar Purkinje cells. Immunoreactivity for GABA was observed on presynaptic and, more abundantly, on postsynaptic compartments, showing both scattered and clustered distribution patterns. Quantitative analysis of immunoparticles revealed a somato-dendritic gradient, with the density of immunoparticles increasing 26-fold from somata to dendritic spines. To understand the spatial relationship of GABA receptors with two key effector ion channels, the G protein-gated inwardly rectifying K (GIRK/Kir3) channel and the voltage-dependent Ca channel, biochemical and immunohistochemical approaches were performed. Co-immunoprecipitation analysis demonstrated that GABA receptors co-assembled with GIRK and Ca2.1 channels in the cerebellum. Using double-labelling immunoelectron microscopic techniques, co-clustering between GABA and GIRK2 was detected in dendritic spines, whereas they were mainly segregated in the dendritic shafts. In contrast, co-clustering of GABA and Ca2.1 was detected in dendritic shafts but not spines. Presynaptically, although no significant co-clustering of GABA and GIRK2 or Ca2.1 channels was detected, inter-cluster distance for GABA and GIRK2 was significantly smaller in the active zone than in the dendritic shafts, and that for GABA and Ca2.1 was significantly smaller in the active zone than in the dendritic shafts and spines. Thus, GABA receptors are associated with GIRK and Ca2.1 channels in different subcellular compartments. These data provide a better framework for understanding the different roles played by GABA receptors and their effector ion channels in the cerebellar network.
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http://dx.doi.org/10.1007/s00429-017-1568-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869904PMC
April 2018

GABA receptor subtypes differentially regulate thalamic spindle oscillations.

Neuropharmacology 2018 07 26;136(Pt A):106-116. Epub 2017 Oct 26.

Dept. Biomedicine, Institute of Physiology, University of Basel, 4056 Basel, Switzerland. Electronic address:

Following the discovery of GABA receptors by Norman Bowery and colleagues, cloning and biochemical efforts revealed that GABA receptors assemble multi-subunit complexes composed of principal and auxiliary subunits. The principal receptor subunits GABA, GABA and GABA form two heterodimeric GABA and GABA receptors that can associate with tetramers of auxiliary KCTD (K channel tetramerization domain) subunits. Experiments with subunit knock-out mice revealed that GABA receptors activate slow inhibitory postsynaptic currents (sIPSCs) while GABA receptors function as heteroreceptors and inhibit glutamate release. Both GABA and GABA receptors can serve as autoreceptors and inhibit GABA release. Auxiliary KCTD subunits regulate the duration of sIPSCs and scaffold effector channels at the receptor. GABA receptors are well known to contribute to thalamic spindle oscillations. Spindles are generated through alternating burst-firing in reciprocally connected glutamatergic thalamocortical relay (TCR) and GABAergic thalamic reticular nucleus (TRN) neurons. The available data implicate postsynaptic GABA receptors in TCR cells in the regulation of spindle frequency. We now used electrical or optogenetic activation of thalamic spindles and pharmacological experiments in acute slices of knock-out mice to study the impact of GABA and GABA receptors on spindle oscillations. We found that selectively GABA heteroreceptors at TCR to TRN cell synapses regulate oscillation strength, while GABA receptors control oscillation frequency. The auxiliary subunit KCTD16 influences both oscillation strength and frequency, supporting that KCTD16 regulates network activity through GABA and GABA receptors. This article is part of the "Special Issue Dedicated to Norman G. Bowery".
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http://dx.doi.org/10.1016/j.neuropharm.2017.10.033DOI Listing
July 2018

Nicotine-induced molecular alterations are modulated by GABA receptor activity.

Addict Biol 2018 01 17;23(1):230-246. Epub 2017 Apr 17.

CONICET - Universidad de Buenos Aires, Instituto de Investigaciones Farmacológicas (ININFA), Buenos Aires, Argentina.

It has been demonstrated that GABA receptors modulate nicotine (NIC) reward effect; nevertheless, the mechanism implicated is not well known. In this regard, we evaluated the involvement of GABA receptors on the behavioral, neurochemical, biochemical and molecular alterations associated with the rewarding effects induced by NIC in mice, from a pharmacological and genetic approach. NIC-induced rewarding properties (0.5 mg/kg, subcutaneously, sc) were evaluated by conditioned place preference (CPP) paradigm. CPP has three phases: preconditioning, conditioning and postconditioning. GABA receptor antagonist 2-hydroxysaclofen (0.25, 0.5 and 1 mg/kg; intraperitoneally, ip) or the GABA receptor agonist baclofen (3 mg/kg; ip) was injected before NIC during the conditioning phase. GABA knockout (GABA KO) mice received NIC during the conditioning phase. Vehicle and wild-type controls were employed. Neurochemical (dopamine, serotonin and their metabolites), biochemical (nicotinic receptor α4β2, α4β2nAChRs) and molecular (c-Fos) alterations induced by NIC were analyzed after the postconditioning phase by high-performance liquid chromatography (HPLC), receptor-ligand binding assays and immunohistochemistry, respectively, in nucleus accumbens (Acb), prefrontal cortex (PFC) and ventral tegmental area (VTA). NIC induced rewarding effects in the CPP paradigm and increased dopamine levels in Acb and PFC, α4β2nAChRs density in VTA and c-Fos expression in Acb shell (AcbSh), VTA and PFC. We showed that behavioral, neurochemical, biochemical and molecular alterations induced by NIC were prevented by baclofen. However, in 2-hydroxysaclofen pretreated and GABA KO mice, these alterations were potentiated, suggesting that GABA receptor activity is necessary to control alterations induced by NIC-induced rewarding effects. Therefore, the present findings provided important contributions to the mechanisms implicated in NIC-induced rewarding effects.
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http://dx.doi.org/10.1111/adb.12506DOI Listing
January 2018

Ionotropic AMPA-type glutamate and metabotropic GABA receptors: determining cellular physiology by proteomes.

Curr Opin Neurobiol 2017 08 7;45:16-23. Epub 2017 Mar 7.

Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Straße 7, 79104 Freiburg, Germany; Center for Biological Signaling Studies (BIOSS), Schänzlestraße 18, 79104 Freiburg, Germany. Electronic address:

Ionotropic AMPA-type glutamate receptors and G-protein-coupled metabotropic GABA receptors are key elements of neurotransmission whose cellular functions are determined by their protein constituents. Over the past couple of years unbiased proteomic approaches identified comprehensive sets of protein building blocks of these two types of neurotransmitter receptors in the brain (termed receptor proteomes). This provided the opportunity to match receptor proteomes with receptor physiology and to study the structural organization, regulation and function of native receptor complexes in an unprecedented manner. In this review we discuss the principles of receptor architecture and regulation emerging from the functional characterization of the proteomes of AMPA and GABA receptors. We also highlight progress in unraveling the role of unexpected protein components for receptor physiology.
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http://dx.doi.org/10.1016/j.conb.2017.02.011DOI Listing
August 2017

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABARs shapes inhibitory neurotransmission.

Nat Commun 2017 03 6;8:14536. Epub 2017 Mar 6.

CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.

Shrm4, a protein expressed only in polarized tissues, is encoded by the KIAA1202 gene, whose mutations have been linked to epilepsy and intellectual disability. However, a physiological role for Shrm4 in the brain is yet to be established. Here, we report that Shrm4 is localized to synapses where it regulates dendritic spine morphology and interacts with the C terminus of GABA receptors (GABARs) to control their cell surface expression and intracellular trafficking via a dynein-dependent mechanism. Knockdown of Shrm4 in rat severely impairs GABAR activity causing increased anxiety-like behaviour and susceptibility to seizures. Moreover, Shrm4 influences hippocampal excitability by modulating tonic inhibition in dentate gyrus granule cells, in a process involving crosstalk between GABARs and extrasynaptic δ-subunit-containing GABARs. Our data highlights a role for Shrm4 in synaptogenesis and in maintaining GABAR-mediated inhibition, perturbation of which may be responsible for the involvement of Shrm4 in cognitive disorders and epilepsy.
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http://dx.doi.org/10.1038/ncomms14536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343488PMC
March 2017

Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior.

Nat Neurosci 2017 Mar 23;20(3):438-448. Epub 2017 Jan 23.

Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.

Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABA receptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABA receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.
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http://dx.doi.org/10.1038/nn.4482DOI Listing
March 2017

Blunted 5-HT receptor-mediated responses and antidepressant-like behavior in mice lacking the GABA but not GABA subunit isoforms.

Psychopharmacology (Berl) 2017 05 9;234(9-10):1511-1523. Epub 2017 Jan 9.

APC Microbiome Institute, University College Cork, Cork, Ireland.

Rationale: There is accumulating evidence for a role of GABA receptors in depression. GABA receptors are heterodimers of GABA and GABA receptor subunits. The predominant GABA subunit isoforms are GABA and GABA. GABA isoforms in mice differentially influence cognition, conditioned fear, and susceptibility to stress, yet their influence in tests of antidepressant-like activity has not been fully investigated.

Objectives: Given the interactions between GABA receptors and the serotonergic system and the involvement of 5-HT receptors (5-HTR) in antidepressant action, we sought to evaluate 5-HTR function in GABA and GABA mice.

Methods: GABA and GABA mice were assessed in the forced swim test (FST), and body temperature and hypothalamic-pituitary-adrenal (HPA) responses to the 5-HTR agonist 8-OH-DPAT were determined. Brain 5-HTR expression was assessed by [H]-MPPF and [H]-8-OH-DPAT autoradiography and 5-HTR G-protein coupling by [S]GTP-γ-S autoradiography.

Results: As previously described, GABA mice showed an antidepressant-like profile in the FST. GABA mice also demonstrated profoundly blunted hypothermic and motoric responses to 8-OH-DPAT. Furthermore, 8-OH-DPAT-induced corticosterone and adrenocorticotropic hormone (ACTH) release were both attenuated in GABA mice. Interestingly, [H]-MPPF and [H]-8-OH-DPAT binding was largely unaffected by genotype. [S]GTP-γ-S autoradiography suggested that altered 5-HTR G-protein coupling only partially contributes to the functional presynaptic 5-HTR desensitization, and not at all to the blunted postsynaptic 5-HTR-mediated responses, seen in GABA mice.

Conclusion: These data demonstrate distinct functional links between 5-HTRs and the GABA subunit isoform and suggest that the GABA isoform may be implicated in the antidepressant-like effects of GABA receptor antagonists and in neurobiological mechanisms underlying depression.
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http://dx.doi.org/10.1007/s00213-016-4521-5DOI Listing
May 2017

Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks.

Elife 2016 12 24;5. Epub 2016 Dec 24.

Department of Neuroscience, University of Minnesota, Minneapolis, United States.

Interneurons are critical for proper neural network function and can activate Ca signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABA receptors, potentiation involved astrocyte GABA receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABA receptor () knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.
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http://dx.doi.org/10.7554/eLife.20362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231406PMC
December 2016

KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents.

J Neurosci 2017 02 21;37(5):1162-1175. Epub 2016 Dec 21.

Department of Biomedicine, Institute of Physiology, University of Basel, 4056 Basel, Switzerland,

GABA receptors are the G-protein coupled receptors for the main inhibitory neurotransmitter in the brain, GABA. GABA receptors were shown to associate with homo-oligomers of auxiliary KCTD8, KCTD12, KCTD12b, and KCTD16 subunits (named after their T1 K-channel tetramerization domain) that regulate G-protein signaling of the receptor. Here we provide evidence that GABA receptors also associate with hetero-oligomers of KCTD subunits. Coimmunoprecipitation experiments indicate that two-thirds of the KCTD16 proteins in the hippocampus of adult mice associate with KCTD12. We show that the KCTD proteins hetero-oligomerize through self-interacting T1 and H1 homology domains. Bioluminescence resonance energy transfer measurements in live cells reveal that KCTD12/KCTD16 hetero-oligomers associate with both the receptor and the G-protein. Electrophysiological experiments demonstrate that KCTD12/KCTD16 hetero-oligomers impart unique kinetic properties on G-protein-activated Kir3 currents. During prolonged receptor activation (one min) KCTD12/KCTD16 hetero-oligomers produce moderately desensitizing fast deactivating K currents, whereas KCTD12 and KCTD16 homo-oligomers produce strongly desensitizing fast deactivating currents and nondesensitizing slowly deactivating currents, respectively. During short activation (2 s) KCTD12/KCTD16 hetero-oligomers produce nondesensitizing slowly deactivating currents. Electrophysiological recordings from hippocampal neurons of KCTD knock-out mice are consistent with these findings and indicate that KCTD12/KCTD16 hetero-oligomers increase the duration of slow IPSCs. In summary, our data demonstrate that simultaneous assembly of distinct KCTDs at the receptor increases the molecular and functional repertoire of native GABA receptors and modulates physiologically induced K current responses in the hippocampus.

Significance Statement: The KCTD proteins 8, 12, and 16 are auxiliary subunits of GABA receptors that differentially regulate G-protein signaling of the receptor. The KCTD proteins are generally assumed to function as homo-oligomers. Here we show that the KCTD proteins also assemble hetero-oligomers in all possible dual combinations. Experiments in live cells demonstrate that KCTD hetero-oligomers form at least tetramers and that these tetramers directly interact with the receptor and the G-protein. KCTD12/KCTD16 hetero-oligomers impart unique kinetic properties to GABA receptor-induced Kir3 currents in heterologous cells. KCTD12/KCTD16 hetero-oligomers are abundant in the hippocampus, where they prolong the duration of slow IPSCs in pyramidal cells. Our data therefore support that KCTD hetero-oligomers modulate physiologically induced K current responses in the brain.
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http://dx.doi.org/10.1523/JNEUROSCI.2181-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596860PMC
February 2017

Organization and functions of mGlu and GABA receptor complexes.

Nature 2016 12;540(7631):60-68

Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.

The neurotransmitters glutamate and γ-aminobutyric acid (GABA) transmit synaptic signals by activating fast-acting ligand-gated ion channels and more slowly acting G-protein-coupled receptors (GPCRs). The GPCRs for these neurotransmitters, metabotropic glutamate (mGlu) and GABA receptors, are atypical GPCRs with a large extracellular domain and a mandatory dimeric structure. Recent studies have revealed how these receptors are activated through multiple allosteric interactions between subunit domains. It emerges that the molecular complexity of these receptors is further increased through association with trafficking, effector and regulatory proteins. The structure and composition of these receptors present opportunities for therapeutic intervention in mental health and neurological disorders.
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http://dx.doi.org/10.1038/nature20566DOI Listing
December 2016

Behavioural endophenotypes in mice lacking the auxiliary GABA receptor subunit KCTD16.

Behav Brain Res 2017 01 4;317:393-400. Epub 2016 Oct 4.

Preclinical Laboratory for Translational Research into Affective Disorders (PLaTRAD), Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland. Electronic address:

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the pathophysiology of a number of neuropsychiatric disorders. The GABA receptors are G-protein coupled receptors consisting of principle subunits and auxiliary potassium channel tetramerization domain (KCTD) subunits. The KCTD subunits 8, 12, 12b and 16 are cytosolic proteins that determine the kinetics of the GABA receptor response. Previously, we demonstrated that Kctd12 null mutant mice (Kctd12) exhibit increased auditory fear learning and that Kctd12 mice show altered circadian activity, as well as increased intrinsic excitability in hippocampal pyramidal neurons. KCTD16 has been demonstrated to influence neuronal excitability by regulating GABA receptor-mediated gating of postsynaptic ion channels. In the present study we investigated for behavioural endophenotypes in Kctd16 and Kctd16 mice. Compared with wild-type (WT) littermates, auditory and contextual fear conditioning were normal in both Kctd16 and Kctd16 mice. When fear memory was tested on the following day, Kctd16 mice exhibited less extinction of auditory fear memory relative to WT and Kctd16 mice, as well as more contextual fear memory relative to WT and, in particular, Kctd16 mice. Relative to WT, both Kctd16 and Kctd16 mice exhibited normal circadian activity. This study adds to the evidence that auxillary KCTD subunits of GABA receptors contribute to the regulation of behaviours that could constitute endophenotypes for hyper-reactivity to aversive stimuli in neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.bbr.2016.10.006DOI Listing
January 2017