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α-Conotoxin Vc1.1 is a small disulfide-bonded peptide from the venom of the marine cone snail . Vc1.1 has antinociceptive actions in animal models of neuropathic pain, but its applicability to inhibiting human dorsal root ganglion (DRG) neuroexcitability and reducing chronic visceral pain (CVP) is unknown. We determined the inhibitory actions of Vc1.1 on human DRG neurons and on mouse colonic sensory afferents in healthy and chronic visceral hypersensitivity (CVH) states. In mice, visceral nociception was assessed by neuronal activation within the spinal cord in response to noxious colorectal distension (CRD). Quantitative-reverse-transcription-PCR, single-cell-reverse-transcription-PCR and immunohistochemistry determined γ-aminobutyric acid receptor B (GABA R) and voltage-gated calcium channel (Ca 2.2, Ca 2.3) expression in human and mouse DRG neurons. Vc1.1 reduced the excitability of human DRG neurons, whereas a synthetic Vc1.1 analogue that is inactive at GABA R did not. Human DRG neurons expressed GABA R and its downstream effector channels Ca 2.2 and Ca 2.3. Mouse colonic DRG neurons exhibited high GABA R, Ca 2.2 and Ca 2.3 expression, with upregulation of the Ca 2.2 exon-37a variant during CVH. Vc1.1 inhibited mouse colonic afferents ex vivo and nociceptive signalling of noxious CRD into the spinal cord in vivo, with greatest efficacy observed during CVH. A selective GABA R antagonist prevented Vc1.1-induced inhibition, whereas blocking both Ca 2.2 and Ca 2.3 caused inhibition comparable with Vc1.1 alone. Vc1.1-mediated activation of GABA R is a novel mechanism for reducing the excitability of human DRG neurons. Vc1.1-induced activation of GABA R on the peripheral endings of colonic afferents reduces nociceptive signalling. The enhanced antinociceptive actions of Vc1.1 during CVH suggest it is a novel candidate for the treatment for CVP.

Disulfide trapping and FRET studies define an agonist-induced conformational change in mGlu2 from inactive symmetric dimers with an interface at transmembrane domains (TMs) 4 and 5 to an active state with TM6s serving as the dimer interface. G protein–coupled receptors (GPCRs) are major players in cell communication. Although they form functional monomers, increasing evidence indicates that GPCR dimerization has a critical role in cooperative phenomena that are important for cell signal integration. However, the structural bases of these phenomena remain elusive. Here, using well-characterized receptor dimers, the metabotropic glutamate receptors (mGluRs), we show that structural changes at the dimer interface are linked to receptor activation. We demonstrate that the main dimer interface is formed by transmembrane α helix 4 (TM4) and TM5 in the inactive state and by TM6 in the active state. This major change in the dimer interface is required for receptor activity because locking the TM4-TM5 interface prevents activation by agonist, whereas locking the TM6 interface leads to a constitutively active receptor. These data provide important information on the activation mechanism of mGluRs and improve our understanding of the structural basis of the negative cooperativity observed in these GPCR dimers.

GABA interneurons play a critical role in higher brain functions. Astrocytic glial cells interact with synapses throughout the whole brain and are recognized as regulatory elements of excitatory synaptic transmission. However, it is largely unknown how GABAergic interneurons and astrocytes interact and contribute to stable performance of complex behaviors. Here, we found that genetic ablation of GABA B receptors in medial prefrontal cortex astrocytes altered low-gamma oscillations and firing properties of cortical neurons, which affected goal-directed behaviors. Remarkably, working memory deficits were restored by optogenetic stimulation of astrocytes with melanopsin. Furthermore, melanopsin-activated astrocytes in wild-type mice enhanced the firing rate of cortical neurons and gamma oscillations, as well as improved cognition. Therefore, our work identifies astrocytes as a hub for controlling inhibition in cortical circuits, providing a novel pathway for the behaviorally relevant midrange time-scale regulation of cortical information processing and consistent goal-directed behaviors. Mederos et al. show that GABA B receptor signaling in astrocytes regulates prefrontal cortex activity to impact goal-directed behaviors. Thus, the coordinated activity of GABAergic neurons and astrocytes helps decision-making.

There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABAB1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABAAα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABAAα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut–brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.

Inputs to midbrain dopamine neurons control rewarding and drug-related behaviors. The authors found that nucleus accumbens inputs and local GABA neurons inhibit dopamine neurons through distinct populations of GABA receptors. Furthermore, genetic deletion of GABA B receptors from dopamine neurons selectively increased behavioral sensitivity to cocaine. 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 B 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 B 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.

Biphasic effects of cannabinoids have been shown in processes such as feeding behavior, motor activity, motivational processes and anxiety responses. Using two different tests for the characterization of anxiety-related behavior (elevated plus-maze and holeboard), we first identified in wild-type C57BL/6N mice, two doses of the synthetic CB1 cannabinoid receptor agonist CP-55,940 with anxiolytic (1 μg/kg) and anxiogenic properties (50 μg/kg), respectively. To clarify the role of CB1 receptors in this biphasic effect, both doses were applied to two different conditional CB1 receptor knockout (KO) mouse lines, GABA-CB1-KO (CB1 receptor inactivation in forebrain GABAergic neurons) and Glu-CB1-KO (CB1 receptor inactivation in cortical glutamatergic neurons). We found that the anxiolytic-like effects of the low dose of cannabinoids are mediated via the CB1 receptor on cortical glutamatergic terminals, because this anxiolytic-like response was abrogated only in Glu-CB1-KO mice. On the contrary, the CB1 receptor on the GABAergic terminals is required to induce an anxiogenic-like effect under a high-dose treatment because of the fact that this effect was abolished specifically in GABA-CB1-KO mice. These experiments were carried out in both sexes, and no differences occurred with the doses tested in the mutant mice. Interestingly, the positive allosteric modulation of GABA(B) receptor with GS-39783 was found to largely abrogate the anxiogenic-like effect of the high dose of CP-55,940. Our results shed new light in further understanding the biphasic effects of cannabinoids at the molecular level and, importantly, pave the way for the development of novel anxiolytic cannabinoid drugs, which may have favorable effect profiles targeting the CB1 receptor on glutamatergic terminals.

GABA B receptors are the most abundant inhibitory G protein–coupled receptors in the mammalian brain. Using high-resolution proteomics, the authors show that native GABA B receptors are macromolecular complexes with previously unknown complexity in subunit composition. This molecular diversity in structure and assembly encodes the diversity of GABA B physiology in the CNS. GABA B receptors, the most abundant inhibitory G protein–coupled receptors in the mammalian brain, display pronounced diversity in functional properties, cellular signaling and subcellular distribution. We used high-resolution functional proteomics to identify the building blocks of these receptors in the rodent brain. Our analyses revealed that native GABA B receptors are macromolecular complexes with defined architecture, but marked diversity in subunit composition: the receptor core is assembled from GABA B1a/b , GABA B2 , four KCTD proteins and a distinct set of G-protein subunits, whereas the receptor's periphery is mostly formed by transmembrane proteins of different classes. In particular, the periphery-forming constituents include signaling effectors, such as Cav2 and HCN channels, and the proteins AJAP1 and amyloid-β A4, both of which tightly associate with the sushi domains of GABA B1a . Our results unravel the molecular diversity of GABA B receptors and their postnatal assembly dynamics and provide a roadmap for studying the cellular signaling of this inhibitory neurotransmitter receptor.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating complication of cisplatin chemotherapy, often manifesting as mechanical allodynia, which frequently resists conventional treatments. This study explored the behavioral and molecular alterations induced by cisplatin, with a focus on regional dysfunction of the gamma-aminobutyric acid (GABA) system, and evaluated the therapeutic potential of intraplantar baclofen (a GABA B receptor agonist) in alleviating CIPN. Rats were administered cisplatin (2 mg/kg, i.p., once weekly for 4 weeks), and behavioral assessments revealed significant mechanical allodynia, with no significant effects on cold or heat sensitivity. Molecular analyses (high-performance liquid chromatography (HPLC), reverse transcription polymerase chain reaction (RT-PCR), and Western blot) demonstrated a region-specific GABAergic imbalance: increased GABA levels and glutamate decarboxylase (GAD) mRNA in the dorsal root ganglia (DRG), alongside decreased GABA levels and downregulated GABA B receptor expression in the hind paw skin. Intraplantar baclofen pretreatment delayed the onset of mechanical allodynia, while post-treatment produced a dose-dependent reversal of symptoms, with no effect on hind paw temperature. These findings suggest that peripheral GABA B receptors are a promising target for topical therapy of CIPN, potentially mediated by regional modulation of the GABAergic system.

Many schizophrenia susceptibility loci have been identified through genome-wide association studies (GWASs) in European populations. However, until recently, schizophrenia GWASs in non-European populations were limited to small sample sizes and have yielded few loci associated with schizophrenia. To identify genetic risk variations for schizophrenia in the Han Chinese population, we performed a two-stage GWAS of schizophrenia comprising 4384 cases and 5770 controls, followed by independent replications of 13 single-nucleotide polymorphisms in an additional 4339 schizophrenia cases and 7043 controls of Han Chinese ancestry. Furthermore, we conducted additional analyses based on the results in the discovery stage. The combined analysis confirmed evidence of genome-wide significant associations in the Han Chinese population for three loci, at 2p16.1 (rs1051061, in an exon of VRK2 , P =1.14 × 10 −12 , odds ratio (OR)=1.17), 6p22.1 (rs115070292 in an intron of GABBR1 , P =4.96 × 10 −10 , OR=0.77) and 10q24.32 (rs10883795 in an intron of AS3MT , P =7.94 × 10 −10 , OR=0.87; rs10883765 at an intron of ARL3 , P =3.06 × 10 −9 , OR=0.87). The polygenic risk score based on Psychiatric Genomics Consortium schizophrenia GWAS data modestly predicted case–control status in the Chinese population (Nagelkerke R 2 : 1.7% ~5.7%). Our pathway analysis suggested that neurological biological pathways such as GABAergic signaling, dopaminergic signaling, cell adhesion molecules and myelination pathways are involved in schizophrenia. These findings provide new insights into the pathogenesis of schizophrenia in the Han Chinese population. Further studies are needed to establish the biological context and potential clinical utility of these findings.

Neurons coordinate inter-tissue protein homeostasis to systemically manage cytotoxic stress. In response to neuronal mitochondrial stress, specific neuronal signals coordinate the systemic mitochondrial unfolded protein response (UPR mt ) to promote organismal survival. Yet, whether chemical neurotransmitters are sufficient to control the UPR mt in physiological conditions is not well understood. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPR mt in the Caenorhabditis elegans intestine. GABA controls the UPR mt by regulating extra-synaptic ACh release through metabotropic GABA B receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh-degradative enzymes induce the UPR mt through ACR-11, an intestinal nicotinic α7 receptor. This neuro-intestinal circuit is critical for non-autonomously regulating organismal survival of oxidative stress. These findings establish chemical neurotransmission as a crucial regulatory layer for nervous system control of systemic protein homeostasis and stress responses. Here, Cornell et al . reveal specific neurotransmitters (gamma-aminobutyric acid and acetylcholine) that regulate the ability of animals to manage metabolic stress through an intestinal acetylcholine receptor.