Role Of GABAB Receptors Research Articles

Baclofen and 4-Phenylpyrrolidone Derivative GIZH-290 Attenuates Compulsive-Like Behavior in Mice

Obsessive-compulsive disorder (OCD) is a mental disease characterized by the obsessions which cause marked distress or anxiety and/or compulsions intended to alleviate this distress. The results of experimental and clinical studies suggest a possible role of GABAB receptors in the pathogenesis of OCD, making it relevant to study the effect of ligands of these receptors on the behavior of rodents. Objectives: Studying the effects of GIZH-290 and baclofen in animal models of OCD. Methods. The effects of GIZH-290 (0.01, 0.1, 1 mg/kg, i.p.) and baclofen (0.1, 1, and 5 mg/kg, i.p.) were studied in the marble burying test and the rotarod test, as well as in the 8-OH-DPAT-induced decrease in spontaneous alternation in mice. Results. Baclofen and GIZH-290 attenuated compulsive-like behavior in mice by reducing the number of buried marbles in the marble burying test at all tested doses. However, the effect of baclofen at a dose of 5 mg/kg was accompanied by a disruption of the animals’ motor coordination in the rotarod test. At the same time, neither baclofen nor GIZH-290 attenuated 8-OH-DPAT-induced (2 mg/kg, i.p.) decrease in spontaneous alternation behavior in mice. On the contrary, baclofen at a dose of 1 mg/kg exacerbated this disruption. Conclusion. Baclofen and GIZH-290 have anticompulsive activity in the marble burying test, but not in the 8-OH-DPAT-induced decrease in spontaneous alternation behavior in mice.

The role of GABAB receptors in the subcortical pathways of the mammalian auditory system.

GABAB receptors are G-protein coupled receptors for the inhibitory neurotransmitter GABA. Functional GABAB receptors are formed as heteromers of GABAB1 and GABAB2 subunits, which further associate with various regulatory and signaling proteins to provide receptor complexes with distinct pharmacological and physiological properties. GABAB receptors are widely distributed in nervous tissue, where they are involved in a number of processes and in turn are subject to a number of regulatory mechanisms. In this review, we summarize current knowledge of the cellular distribution and function of the receptors in the inner ear and auditory pathway of the mammalian brainstem and midbrain. The findings suggest that in these regions, GABAB receptors are involved in processes essential for proper auditory function, such as cochlear amplifier modulation, regulation of spontaneous activity, binaural and temporal information processing, and predictive coding. Since impaired GABAergic inhibition has been found to be associated with various forms of hearing loss, GABAB dysfunction could also play a role in some pathologies of the auditory system.

Extracellular\xa0Signal-Regulated Kinases Mediate an Autoregulation of GABAB-Receptor-Activated Whole-Cell Current in Locus Coeruleus Neurons

The norepinephrine-releasing neurons in the locus coeruleus (LC) are well known to regulate wakefulness/arousal. They display active firing during wakefulness and a decreased discharge rate during sleep. We have previously reported that LC neurons express large numbers of GABAB receptors (GABABRs) located at peri-/extrasynaptic sites and are subject to tonic inhibition due to the continuous activation of GABABRs by ambient GABA, which is significantly higher during sleep than during wakefulness. In this study, we further showed using western blot analysis that the activation of GABABRs with baclofen could increase the level of phosphorylated extracellular signal-regulated kinase 1 (ERK1) in LC tissue. Recordings from LC neurons in brain slices showed that the inhibition of ERK1/2 with U0126 and FR180204 accelerated the decay of whole-cell membrane current induced by prolonged baclofen application. In addition, the inhibition of ERK1/2 also increased spontaneous firing and reduced tonic inhibition of LC neurons after prolonged exposure to baclofen. These results suggest a new role of GABABRs in mediating ERK1-dependent autoregulation of the stability of GABABR-activated whole-cell current, in addition to its well-known effect on gated potassium channels, to cause a tonic current in LC neurons.

Role of GABAB receptors in proepileptic and antiepileptic effects of an applied electric field in rat hippocampus in vitro

The mechanisms underlying antiepileptic effects of deep brain stimulation (DBS) are complex and poorly understood. Studies on the effects of applied electric fields on epileptic nervous tissue could enable future advances in DBS treatments. Applied electric fields are known to inhibit or enhance epileptic activity in vitro through direct effects on local neurons, but it is unclear whether trans-synaptic effects participate in such actions. The present study investigates, in an epileptic brain slice model, the influence of GABAB receptor activation on excitatory and suppressive effects of a short-duration (10 ms) electric field in rat hippocampus. The results show that perfusion of the GABAB receptor antagonist, CGP 55845 (2 μM), could abolish applied-field induced suppression of orthodromic-stimulus evoked epileptiform afterdischarge activity in the CA1 region. GABAB receptor blockade was associated with an enhanced excitatory (proepileptic) effect of the applied field. However, the suppressive effect, observed in isolation using weak field stimuli, was left unchanged. The G-protein-activated inwardly rectifying K+ channel (GIRK) antagonist, tertiapin (30–50 nM), mimicked the effects of CGP 55845. The results suggest that the applied field activate (elements of) local interneurons to release GABA onto GABAB receptors. The resulting activation of postsynaptic GIRK channels inhibits neuronal activity thereby dampening the direct stimulatory effect of the applied field. The study indicates that local-stimulus induced GABAB receptor activation can serve a protective role under antiepileptic paradigms by preventing electrical stimulation from causing hyperexcitation.

Blunted 5-HT1A receptor-mediated responses and antidepressant-like behavior in mice lacking the GABAB1a but not GABAB1b subunit isoforms.

There is accumulating evidence for a role of GABAB receptors in depression. GABAB receptors are heterodimers of GABAB1 and GABAB2 receptor subunits. The predominant GABAB1 subunit isoforms are GABAB1a and GABAB1b. GABAB1 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. Given the interactions between GABAB receptors and the serotonergic system and the involvement of 5-HT1A receptors (5-HT1AR) in antidepressant action, we sought to evaluate 5-HT1AR function in GABAB1a-/- and GABAB1b-/- mice. GABAB1a-/- and GABAB1b-/- mice were assessed in the forced swim test (FST), and body temperature and hypothalamic-pituitary-adrenal (HPA) responses to the 5-HT1AR agonist 8-OH-DPAT were determined. Brain 5-HT1AR expression was assessed by [3H]-MPPF and [3H]-8-OH-DPAT autoradiography and 5-HT1AR G-protein coupling by [35S]GTP-γ-S autoradiography. As previously described, GABAB1a-/- mice showed an antidepressant-like profile in the FST. GABAB1a-/- 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 GABAB1a-/- mice. Interestingly, [3H]-MPPF and [3H]-8-OH-DPAT binding was largely unaffected by genotype. [35S]GTP-γ-S autoradiography suggested that altered 5-HT1AR G-protein coupling only partially contributes to the functional presynaptic 5-HT1AR desensitization, and not at all to the blunted postsynaptic 5-HT1AR-mediated responses, seen in GABAB1a-/- mice. These data demonstrate distinct functional links between 5-HT1ARs and the GABAB1a subunit isoform and suggest that the GABAB1a isoform may be implicated in the antidepressant-like effects of GABAB receptor antagonists and in neurobiological mechanisms underlying depression.

Sex difference in the contribution of GABAB receptors to tibial neuromodulation of bladder overactivity in cats.

This study investigated the role of γ-aminobutyric acid subtype B (GABAB) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical administration of dilute (0.5%) acetic acid (AA) in α-chloralose-anesthetized cats. To inhibit bladder overactivity, tibial or pudendal nerve stimulation (TNS or PNS) was applied at 5 Hz and two or four times threshold (T) intensity for inducing toe or anal sphincter twitch. TNS at 2T or 4T intensity significantly (P < 0.05) increased the bladder capacity to 173.8 ± 16.2 or 198.5 ± 24.1%, respectively, of control capacity. Meanwhile, PNS at 2T or 4T intensity significantly (P < 0.05) increased the bladder capacity to 217 ± 18.8 and 221.3 ± 22.3% of control capacity, respectively. CGP52432 (a GABAB receptor antagonist) at intravenous dosages of 0.1-1 mg/kg completely removed the TNS inhibition in female cats but had no effect in male cats. CGP52432 administered intravenously also had no effect on control bladder capacity or the pudendal inhibition of bladder overactivity. These results reveal a sex difference in the role of GABAB receptors in tibial neuromodulation of bladder overactivity in cats and that GABAB receptors are not involved in either pudendal neuromodulation or irritation-induced bladder overactivity.

GABAB Receptors as Modulating Target for Inflammatory Responses of the Periodontal Ligament.

PDL cells express GABAB1 and GABAB2 receptors, which are regulated by inflammation and thus might be implicated in periodontal immunology. It was the aim of this study to elucidate the functional role of GABAB receptors in immunomodulation regarding activation of proregenerative versus proinflammatory mechanisms. Human PDL cells were exposed to GABA and/or GABAB receptor antagonist CGP-52432 alone or in combination with IL-1β to mimic inflammation. The influence on marker expression for inflammatory tissue destruction was determined via qRT-PCR and Luminex assays. Proliferation and biomineralization were assessed by MTS assay and von Kossa staining. Statistical significance was set at p<0.05. GABAB receptor blockade inhibited expression of IL-6, TNFα, MMP-3, and MMP-8 in an inflammatory milieu on transcriptional and on protein level, mediated by NF-κB. Besides, receptor blockade enhanced proliferation, especially under inflammatory conditions, and reduced mineralization in a non-inflammatory milieu. GABAB receptor activity on PDL cells is involved in the modulation of osteoimmunological processes in the periodontium and decides on the initiation versus prevention of host protective mechanisms. This implies anabolic potential for a therapeutic preservation or reestablishment of periodontal tissues under physiological and pathological conditions. In summary, GABAB receptor modulation in PDL cells might become an important target in immunoinflammatory settings.

GABAB receptor plasticity in corticotrophin releasing hormone neurons in the paraventricular nucleus during chronic unpredictable stress

GABAB (γ‐aminobutytic acid type B) receptor is important in the regulation of neuronal excitability. Chronic stress leads to hyperactivity of corticotrophin releasing hormone (CRH) neurons. However, the role of GABAB receptors in the regulation of CRH neurons in paraventricular nucleus (PVN) of the hypothalamus in chronic stress is not known. Here, we determined pre‐ and postsynaptic GABAB receptor function in identified PVN‐CRH neurons expressing eGFP driven by crh premotor‐driven eGFP. Whole cell patch‐clamp recording were performed on PVN‐CRH neurons in brain slices from unstressed rats and rats with chronic unpredictable mild stress (CUMS). Bath application of the GABAB receptor agonist baclofen induced a significant lesser reduction of firing activity in PVN‐CRH neurons in CUMS than in unstressed rats. Furthermore, baclofen induced lesser outward currents in PVN‐CRH neurons in CUMS than in unstressed rats. Baclofen‐induced currents were eliminated by inclusion of GDP‐β‐s in internal recording solution or blocking G protein‐coupled inwardly‐rectifying K (GIRK) channels with tertiapin. GABAB1 receptor expression level in the PVN was significantly decreased in CUMS than in unstressed rats. Baclofen produced significant greater inhibition of the frequency of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitor postsynaptic currents (IPSCs) without affecting the amplitude of EPSCs and IPSCs in PVN‐CRH neurons in CUMS and unstressed rats. These data suggest that down‐regulated postsynaptic GABAB receptor contributes to suppressing GABAB‐mediated inhibition of PVN‐CRH neurons in chronic stress.Support or Funding InformationNIMH grants MH096086.

Effects of Nourishing “Yin”-Removing “Fire” Chinese Herb Mixture on the Expression of GABAB Receptors in Hypothalamus of Precocious Puberty Female Rats

Objectives: To investigate the potential role of GABAB Receptors (GABABRs) involved in the effect of Nourishing “Yin”-Removing “Fire” Chinese herb mixture (TCM) treatment on precocious puberty. Methods: Female Sprague-Dawley rats were randomly divided into four groups: normal (N), central precocious puberty (CPP) model (M), CPP fed with normal saline (S) and CPP fed with Nourishing “Yin”-Removing “Fire” Chinese herb mixture (TCM). Rats of postnatal day 5 were given a single subcutaneous injection of 240 μg danazol to establish CPP model rats. Rats of S and TCM groups were continuously administered with saline or nourishing “Yin”-removing “Fire” Chinese herb mixture since postnatal day 15. The expression of GABABRs was detected by means of real-time PCR and immunohistochemistry. Results: The expression of hypothalamic GnRH mRNA in M was significantly increased on the day of pre-puberty when compared with that of N (P B1 receptor (GABABR1) immunoreactive cells in the arcuate nucleus (ARN) was decreased in M when compared with that of N (P B2 receptor (GABABR2) immunoreactive cells in the ARN, MS and diagnonal band of broca (DBB) were decreased in M when compared with those of N (P < 0.05) and increased in TCM compared with those of M (P < 0.05) on the day of onset-puberty. At the same time, the mRNA expression of GABABR2 was significantly decreased in M compared with that of N (P < 0.01). Conclusions: These results indicated that the GABABRs might involve in the curative effect of Nourishing “Yin”-Removing “Fire” Chinese herbal mixture on CPP rats.

Mouse hippocampal GABAB1 but not GABAB2 subunit-containing receptor complex levels are paralleling retrieval in the multiple-T-maze.

GABAB receptors are heterodimeric G-protein coupled receptors known to be involved in learning and memory. Although a role for GABAB receptors in cognitive processes is evident, there is no information on hippocampal GABAB receptor complexes in a multiple T maze (MTM) task, a robust paradigm for evaluation of spatial learning. Trained or untrained (yoked control) C57BL/6J male mice (n = 10/group) were subjected to the MTM task and sacrificed 6 h following their performance. Hippocampi were taken, membrane proteins extracted and run on blue native PAGE followed by immunoblotting with specific antibodies against GABAB1, GABAB1a, and GABAB2. Immunoprecipitation with subsequent mass spectrometric identification of co-precipitates was carried out to show if GABAB1 and GABAB2 as well as other interacting proteins co-precipitate. An antibody shift assay (ASA) and a proximity ligation assay (PLA) were also used to see if the two GABAB subunits are present in the receptor complex. Single bands were observed on Western blots, each representing GABAB1, GABAB1a, or GABAB2 at an apparent molecular weight of approximately 100 kDa. Subsequently, densitometric analysis revealed that levels of GABAB1 and GABAB1a but not GABAB2- containing receptor complexes were significantly higher in trained than untrained groups. Immunoprecipitation followed by mass spectrometric studies confirmed the presence of GABAB1, GABAB2, calcium calmodulin kinases I and II, GluA1 and GluA2 as constituents of the complex. ASA and PLA also showed the presence of the two subunits of GABAB receptor within the complex. It is shown that increased levels of GABAB1 subunit-containing complexes are paralleling performance in a land maze.

Lack of GABAB receptors modifies behavioural and biochemical alterations induced by precipitated nicotine withdrawal

The nicotine (NIC) withdrawal syndrome is considered to be a major cause of the high relapse rate among individuals undergoing smoking cessation. The aim of the present study was to evaluate a possible role of GABAB receptors in NIC withdrawal, by comparing GABAB1 knockout mice and their wild-type littermates. We analysed the time course of the global withdrawal score, the anxiety-like effects, monoamine concentrations, the brain-derived neurotrophic factor (BDNF) expression, the corticosterone plasmatic levels and [3H]epibatidine binding sites during NIC withdrawal precipitated by mecamylamine, a nicotinic receptor antagonist (MEC). In NIC withdrawn wild-type mice, we observed a global withdrawal score, an anxiety-like effect in the elevated plus maze, a decrease of the striatal dopamine and 3,4-dihydroxyphenylacetic acid concentrations, an increase of corticosterone plasma levels, a reduction of BDNF expression in several brain areas and an increase of [3H]epibatidine binding sites in specific brain regions. Interestingly, the effects found in NIC withdrawn wild-type mice were absent in GABAB1 knockout mice, suggesting that GABAB1 subunit of the GABAB receptor is involved in the regulation of the behavioural and biochemical alterations induced by NIC withdrawal in mice. These results reveal an interaction between the GABAB receptors and the neurochemical systems through which NIC exerts its long-term effects.

The role of GABAB receptors in human reinforcement learning

Behavioral evidence from human studies suggests that the γ-aminobutyric acid type B receptor (GABAB receptor) agonist baclofen modulates reinforcement learning and reduces craving in patients with addiction spectrum disorders. However, in contrast to the well established role of dopamine in reinforcement learning, the mechanisms by which the GABAB receptor influences reinforcement learning in humans remain completely unknown. To further elucidate this issue, a cross-over, double-blind, placebo-controlled study was performed in healthy human subjects (N=15) to test the effects of baclofen (20 and 50mg p.o.) on probabilistic reinforcement learning. Outcomes were the feedback-induced P2 component of the event-related potential, the feedback-related negativity, and the P300 component of the event-related potential. Baclofen produced a reduction of P2 amplitude over the course of the experiment, but did not modulate the feedback-related negativity. Furthermore, there was a trend towards increased learning after baclofen administration relative to placebo over the course of the experiment. The present results extend previous theories of reinforcement learning, which focus on the importance of mesolimbic dopamine signaling, and indicate that stimulation of cortical GABAB receptors in a fronto-parietal network leads to better attentional allocation in reinforcement learning. This observation is a first step in our understanding of how baclofen may improve reinforcement learning in healthy subjects. Further studies with bigger sample sizes are needed to corroborate this conclusion and furthermore, test this effect in patients with addiction spectrum disorder.

Regulating hippocampal hyperexcitability through GABAB Receptors.

Abstract Disturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein-coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 μmol/L nor the GABAB receptor agonist baclofen at 0.1 μmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 μmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure-related hyperexcitability.

Regulating hippocampal hyperexcitability through GABAB Receptors

Disturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein‐coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 μmol/L nor the GABAB receptor agonist baclofen at 0.1 μmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 μmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure‐related hyperexcitability.

Attenuation by baclofen of nicotine rewarding properties and nicotine withdrawal manifestations

Nicotine is a major active ingredient in tobacco and plays a major role in tobacco addiction. In rodents, repeated nicotine administration produces behavioral responses related to its addictive properties, such as reinforcing effects and physical dependence. The aim of the present study was to evaluate the possible role of GABAB receptor in responses induced by repeated nicotine administration in Swiss Webster mice. Nicotine hydrogen tartrate salt (0.5mg/kg, s.c.) administration induced rewarding properties in the conditioning place preference test. The GABAB receptor agonist, baclofen (3mg/kg, i.p.) abolished the rewarding properties induced by nicotine hydrogen tartrate salt (0.5mg/kg, s.c.). In addition, naloxone-precipitated nicotine withdrawal induced somatic manifestations, anxiety-like effects in the elevated plus maze test and dysphoric manifestations in the conditioned place aversion paradigm. Baclofen (2 and 3mg/kg, i.p.) prevented the somatic manifestations and the anxiety-like effects associated with naloxone-precipitated nicotine withdrawal but not the dysphoric manifestations. These results showed that nicotine rewarding properties and negative aspects of nicotine withdrawal, such as anxiety-like effects and somatic manifestations, can be modulated by the GABAB receptor activity. This study now reveals a novel possible application of baclofen to develop new therapeutic strategies to achieve smoking cessation.

GABAergic control of central serotonergic neurotransmission – role of GABAB receptors and possible implication in the antidepressant action of ketamine

GABAergic control of central serotonergic neurotransmission – role of GABAB receptors and possible implication in the antidepressant action of ketamine

Acute behavioural responses to nicotine and nicotine withdrawal syndrome are modified in GABAB1 knockout mice

Nicotine is the main active component of tobacco, and has both acute and chronic pharmacological effects that can contribute to its abuse potential in humans. The aim of the present study was to evaluate a possible role of GABAB receptors in acute and chronic responses to nicotine administration, by comparing GABAB1 knockout mice and their wild-type littermates. In wild-type mice, acute nicotine administration (0.5, 1, 3 and 6 mg/kg, sc) dose-dependently decreased locomotor activity, and induced antinociceptive responses in the tail-immersion and hot-plate tests. In GABAB1 knockout mice, the hypolocomotive effect was observed only with the highest dose of nicotine, and the antinociceptive responses in both tests were significantly reduced in GABAB1 knockout mice compared to their wild-type littermate. Additionally, nicotine elicited anxiolytic- (0.05 mg/kg) and anxiogenic-like (0.8 mg/kg) responses in the elevated plus-maze test in wild-type mice, while selectively the anxiolytic-like effect was abolished in GABAB1 knockout mice. We further investigated nicotine withdrawal in mice chronically treated with nicotine (25 mg/kg/day, sc). Mecamylamine (1 mg/kg, sc) precipitated several somatic signs of nicotine withdrawal in wild-type mice. However, signs of nicotine withdrawal were missing in GABAB1 knockout mice. Finally, there was a decreased immunoreactivity of Fos-positive nuclei in the bed nucleus of the stria terminalis, basolateral amygdaloid nucleus and hippocampal dentate gyrus in abstinent wild-type but not in GABAB1 knockout mice. These results reveal an interaction between the GABAB system and the neurochemical systems through which nicotine exerts its acute and long-term effects.

Optical Control of Endogenous Proteins with a Photoswitchable Conditional Subunit Reveals a Role for TREK1 in GABAB Signaling

Selective ligands are lacking for many neuronal signaling proteins. Photoswitched tethered ligands (PTLs) have enabled fast and reversible control of specific proteins containing a PTL anchoring site and have been used to remote control overexpressed proteins. We report here a scheme for optical remote control of native proteins usinga "photoswitchable conditional subunit" (PCS), which contains the PTL anchoring site as well as a mutation that prevents it from reaching the plasma membrane. In cells lacking native subunits for the protein, the PCS remains nonfunctional internally. However, in cells expressing native subunits, the native subunit and PCS coassemble, traffic to the plasma membrane, and place the native protein under optical control provided by the coassembled PCS. We apply this approach to the TREK1 potassium channel, which lacks selective, reversible blockers. We find that TREK1, typically considered to be a leak channel, contributes to the hippocampal GABA(B) response.

In utero knock-down of GABA(B2) receptors affects migration and morphological maturation od pyramidal neurons in the rat somato-sensory cortex

Event Abstract Back to Event In utero knock-down of GABA(B2) receptors affects migration and morphological maturation od pyramidal neurons in the rat somato-sensory cortex G. Bony1*, L. Cancedda1 and A. Contestabile1 1 Italian Institute of Technology, Italy GABA is the principal inhibitory neurotransmitter in the adult brain, and acts through both ionotropic GABAA and metabotropic GABAB receptors (GBR), which are coupled to Ca2+ and K+ (Kir3) channels, and cAMP-signaling. Interestingly, GABAA receptor signaling during early development is mainly depolarizing and excitatory, and GBR lack the inhibitory action of K+ channels. Although excitatory GABAA receptors play a critical function in migration/morphological maturation of neurons, the role of GBR in development remains unknown. Here, we investigated GBR function in pyramidal-neuron progenitors during cor tical development using in utero electroporation coupled with RNA interference. First, we found that GBR knock-down impairs the migration/morphological maturation of pyramidal neurons. Furthermore, field potential recordings of acute slices from rat transfected in utero with RNAi targeting GBR revealed an increase in the length of seizure-like events upon epileptogenic drug treatment. Second, we investigated downstream effectors of GBR. We verified a possible involvement of Kir channels using patch clamp recordings in acute slices of electroporated rats, and a possible contribution of cAMP-signaling by bath application of GBR agonist/antagonist in acute slices from untransfected rats. We found that GBR are not coupled to Kir3 channels during the first postnatal week. Conversely, GBR activation triggers phosphorylation of the cAMP-pathway downstream effector LKB1, a kinase involved in cell polarization. Taken together, our results indicate that GBR play an essential role during cortical development, promoting neuronal migration/morphological maturation in vivo, possibly through axon/dendrite polarization. Conference: EMBO workshop: Gaba Signalling and Brain Networks , Amsterdam, Netherlands, 30 Jun - 2 Jul, 2010. Presentation Type: Poster Presentation Topic: Posters Citation: Bony G, Cancedda L and Contestabile A (2010). In utero knock-down of GABA(B2) receptors affects migration and morphological maturation od pyramidal neurons in the rat somato-sensory cortex. Conference Abstract: EMBO workshop: Gaba Signalling and Brain Networks . doi: 10.3389/conf.fnins.2010.15.00004 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 23 Jun 2010; Published Online: 23 Jun 2010. * Correspondence: G. Bony, Italian Institute of Technology, Genova, Italy, guillaume_1983@live.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers G. Bony L. Cancedda A. Contestabile Google G. Bony L. Cancedda A. Contestabile Google Scholar G. Bony L. Cancedda A. Contestabile PubMed G. Bony L. Cancedda A. Contestabile Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

A role for GABAB receptors in the early stage of vestibular compensation

Event Abstract Back to Event A role for GABAB receptors in the early stage of vestibular compensation Raquel Heskin-Sweezie1*, Heather K. Titley1, Joan Baizer2 and Dianne M. Broussard1, 3, 4 1 University of Toronto, Department of Physiology, Canada 2 University at Buffalo, Department of Physiology and Biophysics, United States 3 University of Toronto, Division of Neurology, Faculty of Medicine, Canada 4 The Toronto Western Hospital, Toronto Western Research Institute, Canada The mechanisms underlying vestibular compensation are not well understood, though evidence suggests that the GABAB receptor may play a role in the recovery process. We sought to determine whether GABAB receptors function in the alleviation of static signs – symptoms that can present themselves without activation of the vestibular reflexes – during the earliest stage of recovery (0-4 hrs after UVD) in mice. We also questioned the role of GABAB receptors in the recovery of the dynamic vestibular reflexes by evaluating balance and gait in conjunction with the manipulation of GABAB receptors at different times between 4 hours and 2 days after UVD. Our mice were divided into groups in which the manipulation of GABABreceptors was carried out through the systemic administration of one of the following test substances: the antagonist CGP56433A, the agonist baclofen, and the positive allosteric modulator CGP7930. The antagonist, CGP56433A, caused the number of static signs to increase significantly between 1.5 and 4 hrs after UVD while baclofen increased the rate at which static signs subsided. CGP7930 had no effect on static signs. None of the test substances had an effect on balance at any time after UVD and gait was affected only at 4 hrs by baclofen and CGP7930. Our results suggest that GABAB receptors function in the earliest stage of vestibular compensation. Also, since the impact of our test substances on recovery in the first few hours did not produce an effect at 2 days, it is possible that the mechanisms underlying the early and late stages of compensation are different from and independent of one another. Conference: B.R.A.I.N. platform in Physiology poster day 2009, Toronto, ON, Canada, 16 Dec - 16 Dec, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Heskin-Sweezie R, Titley HK, Baizer J and Broussard DM (2009). A role for GABAB receptors in the early stage of vestibular compensation. Front. Neurosci. Conference Abstract: B.R.A.I.N. platform in Physiology poster day 2009. doi: 10.3389/conf.neuro.03.2009.17.020 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Dec 2009; Published Online: 17 Dec 2009. * Correspondence: Raquel Heskin-Sweezie, University of Toronto, Department of Physiology, Toronto, Canada, raquel.sweezie@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Raquel Heskin-Sweezie Heather K Titley Joan Baizer Dianne M Broussard Google Raquel Heskin-Sweezie Heather K Titley Joan Baizer Dianne M Broussard Google Scholar Raquel Heskin-Sweezie Heather K Titley Joan Baizer Dianne M Broussard PubMed Raquel Heskin-Sweezie Heather K Titley Joan Baizer Dianne M Broussard Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.