Metabotropic Research Articles

The effect of oestradiol and progesterone on chemerin system expression in the porcine endometrium during early pregnancy and the mid-luteal phase of the oestrous cycle

Chemerin is an adipokine which is the product of the RARRES2 gene expressed mainly in adipose tissue. This hormone exerts biological effects via three metabotropic receptors: chemokine like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C–C chemokine receptor-like 2 (CCRL2). Chemerin exerts pleiotropic effects and participates in the regulation of many processes, such as blood pressure control, immune system regulation, inflammation, and angiogenesis. There is a growing body of evidence to indicate that chemerin is involved in the regulation of reproductive system functions. However, little is known about the regulation of chemerin system (chemerin and its receptors) expression. The authors hypothesized that steroid hormones affect the expression of the chemerin system in the uterus of domestic pigs. Thus, the aim of this study was to investigate the influence of steroids, oestradiol (E2), and progesterone (P4), on the gene (qPCR) and protein (Western blot) expression of chemerin receptors, RARRES2 gene expression as well as chemerin secretion (ELISA) by endometrial slices during early pregnancy (days 10 to 11, 12 to 13, 15 to 16, and 27 to 28) and the mid-luteal phase of the oestrous cycle (days 10 to 11). Both steroid hormones modulated the expression of chemerin receptor genes and proteins, as well as the abundance of RARRES2 mRNA transcripts. The study also demonstrated that E2 increased chemerin protein secretion by endometrial cells during the maternal recognition of pregnancy (days 12 to 13) and decreased its release during embryo implantation (days 15 to 16). P4 had no significant effect on chemerin levels during the studied periods of gestation and the oestrous cycle. These observations suggest that the effects of E2 and P4 on the chemerin system are dependent on the period of gestation or the oestrous cycle. Our results support the hypothesis that the hormonal environment could modulate the expression of the chemerin system in the endometrium.

Optogenetic Prosthetization of Retinal Bipolar Cells

Although the experience of optogenetic retinal prostheticsin animal models dates back to more than 16 years, the first resultsobtained on humans have only been reported in the last year. Over thisperiod, the main challenges of prosthetics became clear and theapproaches to their solution were proposed. In this review, we aimto present the achievements in the field of optogenetic prosthetizationof retinal bipolar cells with a focus mainly on relatively recentpublications. The review addresses the advantages and disadvantagesof bipolar cell prosthetics as compared to the alternative target,retinal ganglion cells, and provides a comparative analysis of theeffectiveness of ionotropic light-sensitive proteins (channelrhodopsins)or metabotropic receptors (rhodopsins) as prosthetic tools.

Fipronil impairs the GABAergic brain responses of Nile Tilapia during the transition from normoxia to acute hypoxia.

γ-aminobutyric acid (GABA) is one of the main neurotransmitters involved in the adaptation processes against the damage that hypoxia can cause to the brain. Due to its antagonist action on GABA receptors, the insecticide fipronil can turn the fish more susceptible to the negative effects of hypoxia. This study aimed to understand better if fipronil affects these GABAergic responses of Tilapia ahead to hypoxia. Oreochromis Niloticus (Nile Tilapia) were exposed for 3 and 8 h to fipronil (0.0, 0.1, and 0.5 µg.L-1 ) under normoxia (dissolved O2 > 6 mg.L-1 ) and moderate hypoxia (dissolved O2 < 2 mg.L-1 ) conditions. Briefly, hypoxia caused opposite effects on the gene transcription of the evaluated ionotropic and metabotropic GABA receptors. Unexpectedly, we obtained reduced HIF1A mRNA and brain GABA levels, mostly in the first 3 h of the experiment, for the hypoxic group compared with the normoxia one. Besides that, we also demonstrated that the insecticide fipronil impairs the brain GABAergic signaling of a hypoxia-tolerant fish during the transition from a normoxic to an acute hypoxic state. Thus, these results predict the relevant impact on the brain metabolic adaptations of fishes exposed to such stressful conditions in an aquatic environment, as well as the effects of fipronil in the GABAergic responses to hypoxia, which in turn may have ecological and physiological significance to hypoxia-tolerant fishes exposed to this insecticide.

Correspondence between gene expression and neurotransmitter receptor and transporter density in the human brain

Neurotransmitter receptors modulate signaling between neurons. Thus, neurotransmitter receptors and transporters play a key role in shaping brain function. Due to the lack of comprehensive neurotransmitter receptor/transporter density datasets, microarray gene expression measuring mRNA transcripts is often used as a proxy for receptor densities. In the present report, we comprehensively test the spatial correlation between gene expression and protein density for a total of 27 neurotransmitter receptors, receptor binding-sites, and transporters across 9 different neurotransmitter systems, using both PET and autoradiography radioligand-based imaging modalities. We find poor spatial correspondences between gene expression and density for all neurotransmitter receptors and transporters except four single-protein metabotropic receptors (5-HT1A, CB1, D2, and MOR). These expression-density associations are related to gene differential stability and can vary between cortical and subcortical structures. Altogether, we recommend using direct measures of receptor and transporter density when relating neurotransmitter systems to brain structure and function.

Enzyme histochemistry: a useful tool for examining the spatial distribution of brain ectonucleotidases in (patho)physiological conditions.

Adenosine 5'-triphosphate (ATP) and other nucleotides and nucleosides, such as adenosine, are versatile signaling molecules involved in many physiological processes and pathological conditions in the nervous system, especially those with an inflammatory component. They can be released from nerve cells, glial cells, and vascular cells into the extracellular space where they exert their function via ionotropic (P2X) or metabotropic (P2Y) receptors. Signaling via extracellular nucleotides and adenosine is regulated by cell-surface located enzymes ectonucleotidases that hydrolyze the nucleotide to the respective nucleoside. This review summarizes a histochemical approach for detection of ectonucleotidase activities in the cryo-sections of brain tissue. The enzyme histochemistry (EHC) might be used as suitable replacement for immunohistochemistry, since it gives information about both localization and activity, thus adding a functional component to a classical histological approach. With this technique, it is possible to visualize spatial distribution and cell-specific localization of ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) and ecto-5'-nucleotidase (eN/CD73) activities during brain development, after different hormonal manipulations, during neurodegeneration, etc. EHC is also suitable for investigation of microglial morphology in different (patho)physiological conditions. Furthermore, the review describes how to quantify EHC results.

Studying Synaptic Connectivity and Strength with Optogenetics and Patch-Clamp Electrophysiology.

Over the last two decades the combination of brain slice patch clamp electrophysiology with optogenetic stimulation has proven to be a powerful approach to analyze the architecture of neural circuits and (experience-dependent) synaptic plasticity in such networks. Using this combination of methods, originally termed channelrhodopsin-assisted circuit mapping (CRACM), a multitude of measures of synaptic functioning can be taken. The current review discusses their rationale, current applications in the field, and their associated caveats. Specifically, the review addresses: (1) How to assess the presence of synaptic connections, both in terms of ionotropic versus metabotropic receptor signaling, and in terms of mono- versus polysynaptic connectivity. (2) How to acquire and interpret measures for synaptic strength and function, like AMPAR/NMDAR, AMPAR rectification, paired-pulse ratio (PPR), coefficient of variance and input-specific quantal sizes. We also address how synaptic modulation by G protein-coupled receptors can be studied with pharmacological approaches and advanced technology. (3) Finally, we elaborate on advances on the use of dual color optogenetics in concurrent investigation of multiple synaptic pathways. Overall, with this review we seek to provide practical insights into the methods used to study neural circuits and synapses, by combining optogenetics and patch-clamp electrophysiology.

GIRK2 Channels in Down Syndrome and Alzheimer's Disease.

Cognitive impairment in Down syndrome (DS) results from the abnormal expression of hundreds of genes. However, the impact of KCNJ6, a gene located in the middle of the 'Down syndrome critical region' of chromosome 21, seems to stand out. KCNJ6 encodes GIRK2 (KIR3.2) subunits of G protein-gated inwardly rectifying potassium channels, which serve as effectors for GABAB, m2, 5HT1A, A1, and many other postsynaptic metabotropic receptors. GIRK2 subunits are heavily expressed in neocortex, cerebellum, and hippocampus. By controlling resting membrane potential and neuronal excitability, GIRK2 channels may thus affect both synaptic plasticity and stability of neural circuits in the brain regions important for learning and memory. Here, we discuss recent experimental data regarding the role of KCNJ6/GIRK2 in neuronal abnormalities and cognitive impairment in models of DS and Alzheimer's disease (AD). The results compellingly show that signaling through GIRK2 channels is abnormally enhanced in mouse genetic models of Down syndrome and that partial suppression of GIRK2 channels with pharmacological or genetic means can restore synaptic plasticity and improve impaired cognitive functions. On the other hand, signaling through GIRK2 channels is downregulated in AD models, such as models of early amyloidopathy. In these models, reduced GIRK2 channel signaling promotes neuronal hyperactivity, causing excitatory-inhibitory imbalance and neuronal death. Accordingly, activation of GABAB/GIRK2 signaling by GIRK channel activators or GABAB receptor agonists may reduce Aβ-induced hyperactivity and subsequent neuronal death, thereby exerting a neuroprotective effect in models of AD.

The role of GABA in islet function.

Gamma aminobutyric acid (GABA) is a non-proteinogenic amino acid and neurotransmitter that is produced in the islet at levels as high as in the brain. GABA is synthesized by the enzyme glutamic acid decarboxylase (GAD), of which the 65 kDa isoform (GAD65) is a major autoantigen in type 1 diabetes. Originally described to be released via synaptic-like microvesicles or from insulin secretory vesicles, beta cells are now understood to release substantial quantities of GABA directly from the cytosol via volume-regulated anion channels (VRAC). Once released, GABA influences the activity of multiple islet cell types through ionotropic GABAA receptors and metabotropic GABAB receptors. GABA also interfaces with cellular metabolism and ATP production via the GABA shunt pathway. Beta cells become depleted of GABA in type 1 diabetes (in remaining beta cells) and type 2 diabetes, suggesting that loss or reduction of islet GABA correlates with diabetes pathogenesis and may contribute to dysfunction of alpha, beta, and delta cells in diabetic individuals. While the function of GABA in the nervous system is well-understood, the description of the islet GABA system is clouded by differing reports describing multiple secretion pathways and effector functions. This review will discuss and attempt to unify the major experimental results from over 40 years of literature characterizing the role of GABA in the islet.

Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice

Alzheimer’s disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABAB receptor signalling through G protein-gated inwardly rectifying K+ (GIRK or Kir3) channels on the hippocampus has been postulated. Thus, we determined the impact of amyloid-β (Aβ) pathology in GIRK channel density, subcellular distribution, and its association with GABAB receptors in hippocampal CA1 pyramidal neurons from the APP/PS1 mouse model using quantitative SDS-digested freeze-fracture replica labelling (SDS-FRL) and proximity ligation in situ assay (P-LISA). In wild type mice, single SDS-FRL detection revealed a similar dendritic gradient for GIRK1 and GIRK2 in CA1 pyramidal cells, with higher densities in spines, and GIRK3 showed a lower and uniform distribution. Double SDS-FRL showed a co-clustering of GIRK2 and GIRK1 in post- and presynaptic compartments, but not for GIRK2 and GIRK3. Likewise, double GABAB1 and GIRK2 SDS-FRL detection displayed a high degree of co-clustering in nanodomains (40–50 nm) mostly in spines and axon terminals. In APP/PS1 mice, the density of GIRK2 and GIRK1, but not for GIRK3, was significantly reduced along the neuronal surface of CA1 pyramidal cells and in axon terminals contacting them. Importantly, GABAB1 and GIRK2 co-clustering was not present in APP/PS1 mice. Similarly, P-LISA experiments revealed a significant reduction in GABAB1 and GIRK2 interaction on the hippocampus of this animal model. Overall, our results provide compelling evidence showing a significant reduction on the cell surface density of pre- and postsynaptic GIRK1 and GIRK2, but not GIRK3, and a decline in GABAB receptors and GIRK2 channels co-clustering in hippocampal pyramidal neurons from APP/PS1 mice, thus suggesting that a disruption in the GABAB receptor–GIRK channel membrane assembly causes dysregulation in the GABAB signalling via GIRK channels in this AD animal model.

The glutamate metabotropic receptor 5 (GRM5) gene is associated with beef cattle home range and movement tortuosity

BackgroundThe grazing behaviour of herbivores and their grazing personalities might in part be determined genetically, but there are few studies in beef cattle illustrating this. In this study, we investigated for first time the genetic variation within a candidate ‘grazing gene’, the glutamate metabotropic receptor 5 gene (GRM5), and tested associations between variation in that gene and variation in grazing personality behaviours (GP-behaviours) displayed by free-ranging cows during winter grazing in the steep and rugged rangelands of New Zealand. Mature beef cows (n = 303, from 3 to 10 years of age) were tracked with global positioning system (GPS) and, with 5-minutes (min) relocation frequency, various GP-behaviours were calculated. These included horizontal and vertical distances travelled, mean elevation, elevation range, elevation gain, slope, home range and movement tortuosity, variously calculated using daily relocation trajectories with repeated measurements (i.e., 7 to 24 days (d)) and satellite-derived digital elevation models (DEM). The different GP-behaviours were fitted into mixed models to ascertain their associations with variant sequences and genotypes of GRM5.ResultsWe discovered three GRM5 variants (A, B and C) and identified the six possible genotypes in the cattle studied. The mixed models revealed that A was significantly associated with elevation range, home range and movement tortuosity. Similarly, GRM5 genotypes were associated (P < 0.05) to home range and movement tortuosity, while trends suggesting association (P < 0.1) were also revealed for elevation range and horizontal distance travelled. Most GP-behaviour models were improved by correcting for cow age-class as a fixed factor. The analysis of GP-behaviours averaged per cow age-class suggests that grazing personality is fully established as beef cows reached 4 years of age. Home range and movement tortuosity were not only associated with GRM5 variation, but also negatively correlated with each other (r = − 0.27, P < 0.001).ConclusionsThere seems to be a genetically determined trade-off between home range and movement tortuosity that may be useful in beef cattle breeding programmes aiming to improve the grazing distribution and utilisation of steep and rugged rangelands.

The Zinc-sensing Receptor (GPR39) Modulates Declarative Memory and Age-related Hippocampal Gene Expression in Male Mice

As a neuromodulator, zinc regulates synaptic plasticity, learning and memory. Synaptic zinc is also a crucial factor in the development of toxic forms of amyloid beta protein and, subsequently, of Alzheimer’s dementia (AD). Therefore, efforts to pinpoint mechanisms underlying zinc-dependent cognitive functions might aid AD research, by providing potential novel targets for drugs. One of the most understudied proteins in this regard is a zinc-sensing metabotropic receptor: GPR39. In this study we investigated the impact of GPR39 knock-out (KO) on age-related memory decline in mice of both sexes, by comparing them to age-matched wild-type (WT) littermates. We also tested the effects of a GPR39 agonist (TC-G 1008) on declarative memory of old animals, and its disruption in adult mice. We observed episodic-like memory (ELM) and spatial memory (SM) deficits in male GPR39 KO mice, as well as intact procedural memory in GPR39 KO mice regardless of age and sex. ELM was also absent in old WT male mice, and all female mice regardless of their genotype. Acute application of TC-G 1008 (10 mg/kg) reversed a deficit in two of three ELM components in old WT male mice, and had no promnesic effect on consolidation interference of ELM in adult WT mice. We discuss the possible neurobiological mechanisms and the translational value of these results for potential add-on pharmacotherapy of AD aimed at the zinc-sensing receptor.

G protein coupling and activation of the metabotropic GABAB heterodimer

Metabotropic γ-aminobutyric acid receptor (GABABR), a class C G protein-coupled receptor (GPCR) heterodimer, plays a crucial role in the central nervous system. Cryo-electron microscopy studies revealed a drastic conformational change upon activation and a unique G protein (GP) binding mode. However, little is known about the mechanism for GP coupling and activation for class C GPCRs. Here, we use molecular metadynamics computations to predict the mechanism by which the inactive GP induces conformational changes in the GABABR transmembrane domain (TMD) to form an intermediate pre-activated state. We find that the inactive GP first interacts with TM3, which further leads to the TMD rearrangement and deeper insertion of the α5 helix that causes the Gα subunit to open, releasing GDP, and forming the experimentally observed activated structure. This mechanism provides fresh insights into the mechanistic details of class C GPCRs activation expected to be useful for designing selective agonists and antagonists.

Ionotropic P2X4 and P2X7 receptors in the regulation of ion transport across rat colon.

ATP plays an important role as an extracellular messenger acting via different types of purinoceptors. Whereas most of the actions of ATP at intestinal epithelia are thought to be mediated by metabotropic P2Y receptors, the role of ionotropic P2X receptors remains unclear. Consequently, we investigated the role of P2X4 and P2X7 receptors on ion transport across rat colonic epithelia by using BzATP, a potent agonist at P2X7 (and weak agonist at P2X4). Ussing chamber and Ca2+ imaging experiments were performed on rat colonic epithelia, combined with P2X receptor expression studies. Ussing chamber experiments revealed that serosal BzATP induced a neuronally mediated increase in short-circuit current caused by Cl- secretion. In contrast, the effect of mucosal BzATP was smaller, insensitive to tetrodotoxin and Cl- -independent. When epithelia were basolaterally depolarized to measure currents across the apical membrane, BzATP stimulated a cation current consistent with the activation of apical nonselective cation channels. Experiments with isolated colonic crypts revealed a BzATP-induced increase in the cytosolic Ca2+ concentration. Sensitivity to antagonists indicates stimulation of P2X4 and P2X7 receptors by serosal BzATP and of P2X7 receptors by mucosal BzATP. A similar pattern was observed with native ATP, which induced larger transepithelial currents in comparison to BzATP. RT-PCR and immunohistochemistry experiments confirmed the expression of P2X4 and P2X7 receptors in the colon localized in the epithelium and in submucosal ganglia. Epithelial and neuronal ionotropic P2X receptors are involved in the regulation of intestinal ion transport.

Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum.

The trace amine-associated receptor 1 (TAAR1) is a Gs protein-coupled, intracellularly located metabotropic receptor. Trace and classic amines, amphetamines, act as agonists on TAAR1; they activate downstream signal transduction influencing neurotransmitter release via intracellular phosphorylation. Our aim was to check the effect of the catecholaminergic activity enhancer compound ((−)BPAP, (R)-(−)-1-(benzofuran-2-yl)-2-propylaminopentane) on neurotransmitter release via the TAAR1 signaling. Rat striatal slices were prepared and the resting and electrical stimulation-evoked [3H]dopamine release was measured. The releaser (±)methamphetamine evoked non-vesicular [3H]dopamine release in a TAAR1-dependent manner, whereas (−)BPAP potentiated [3H]dopamine release with vesicular origin via TAAR1 mediation. (−)BPAP did not induce non-vesicular [3H]dopamine release. N-Ethylmaleimide, which inhibits SNARE core complex disassembly, potentiated the stimulatory effect of (−)BPAP on vesicular [3H]dopamine release. Subsequent analyses indicated that the dopamine-release stimulatory effect of (−)BPAP was due to an increase in PKC-mediated phosphorylation. We have hypothesized that there are two binding sites present on TAAR1, one for the releaser and one for the enhancer compounds, and they activate different PKC-mediated phosphorylation leading to the evoking of non-vesicular and vesicular dopamine release. (−)BPAP also increased VMAT2 operation enforcing vesicular [3H]dopamine accumulation and release. Vesicular dopamine release promoted by TAAR1 evokes activation of D2 dopamine autoreceptor-mediated presynaptic feedback inhibition. In conclusion, TAAR1 possesses a triggering role in both non-vesicular and vesicular dopamine release, and the mechanism of action of (−)BPAP is linked to the activation of TAAR1 and the signal transduction attached.

Meeting report: Flux-independent signaling by ionotropic receptors: Unforeseen roles, complexities, and challenges

The receptors that mediate neurotransmission were organized by the end of the 1970′s into ionotropic and metabotropic receptors by the Nobel laurate Jhon Eccles and his colleague Patrick McGeer (1). Nevertheless, almost 2 decades later, it was reported that the AMPA glutamate receptor elicits what has been called metabotropic-like, noncanonical, nonconducting, nonionotropic or flux-independent activities (2). In the following years, other glutamate receptors were also found to elicit this kind of signaling in the central nervous system (CNS) context, the kainate receptor first and then the N-methyl D-aspartate receptor (NMDAR) (3–5).

Selective block of adenosine A2A receptors prevents ischaemic-like effects induced by oxygen and glucose deprivation in rat medium spiny neurons.

Ischaemia is known to cause massive neuronal depolarization, termed anoxic depolarization (AD), due to energy failure and loss of membrane ion gradients. The neuromodulator adenosine accumulates extracellularly during ischaemia and activates four metabotropic receptors: A1 , A2A , A2B and A3 . Striatal medium spiny neurons (MSNs) express high levels of A2A receptors and are particularly vulnerable to ischaemic insults. A2A Receptor blockade reduces acute striatal post-ischaemic damage but the cellular mechanisms involved are still unknown. We performed patch-clamp recordings of MSNs in rat striatal slices subjected to oxygen and glucose deprivation (OGD) to investigate the effects of A2A receptor ligands or ion channel blockers on AD and OGD-induced ionic imbalance, measured as a positive shift in Erev of ramp currents. Our data indicate that the A2A receptor antagonist SCH58261 (10μM) significantly attenuated ionic imbalance and AD appearance in MSNs exposed to OGD. The K+ channel blocker Ba2+ (2mM) or the Na+ channel blocker tetrodotoxin (1μM) exacerbated and attenuated, respectively, OGD-induced changes. Spontaneous excitatory post-synaptic current (sEPSC) analysis in MSNs revealed that the A2A receptor agonist CGS21680 (1μM) prevented OGD-induced decrease of sEPSCs within the first 5min of the insult, an effect shared by the K+ channel blocker Ba2+ , indicating facilitated glutamate release. Adenosine, released during striatal OGD, activates A2A receptors that may exacerbate OGD-induced damage through K+ channel inhibition. Our results could help to develop A2A receptor-selective therapeutic tools for the treatment of brain ischaemia.

CaMKII T286 phosphorylation has distinct essential functions in three forms of long-term plasticity

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates long-term potentiation or depression (LTP or LTD) after distinct stimuli of hippocampal NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD prevails in juvenile mice, but a mechanistically different form of LTD can be readily induced in adults by instead stimulating metabotropic glutamate receptors (mGluRs). However, the role that CaMKII plays in the mGluR-dependent form of LTD is not clear. Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation (pT286), which induces Ca2+-independent autonomous kinase activity. In addition, we compared the role of pT286 among three forms of long-term plasticity (NMDAR-dependent LTP and LTD, and mGluR-dependent LTD) using simultaneous live imaging of endogenous CaMKII together with synaptic marker proteins. We determined that after LTP stimuli, pT286 autophosphorylation accelerated CaMKII movement to excitatory synapses. After NMDAR-LTD stimuli, pT286 was strictly required for any movement to inhibitory synapses. Similar to NMDAR-LTD, we found the mGluR-LTD stimuli did not induce CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, we demonstrate that the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Thus, despite its prominent role in LTP, we conclude that CaMKII T286 autophosphorylation is also required for both major forms of hippocampal LTD, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.

A synaptic signal for novelty processing in the hippocampus

Episodic memory formation and recall are complementary processes that rely on opposing neuronal computations in the hippocampus. How this conflict is resolved in hippocampal circuits is unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice trained to explore and distinguish between familiar and novel virtual environments. We find that granule cells consistently show a small transient depolarisation upon transition to a novel environment. This synaptic novelty signal is sensitive to local application of atropine, indicating that it depends on metabotropic acetylcholine receptors. A computational model suggests that the synaptic response to novelty may bias granule cell population activity, which can drive downstream attractor networks to a new state, favouring the switch from recall to new memory formation when faced with novelty. Such a novelty-driven switch may enable flexible encoding of new memories while preserving stable retrieval of familiar ones.

A Review of Glutamate and Its Receptors: Their Roles in Brain Physiology and Pathology

Glutamate is the most abundant excitatory neurotransmitter in the central nervous system. Through its ionotropic and metabotropic receptors it mediates both fast transmission and long term metabolic changes in a cell. Besides neurotransmission, it takes part in development of central nervous system, cell energy metabolism and synaptic plasticity processes. Glutamatergic signaling is strictly controlled. Under normal conditions, extrasynaptic gluatamate levels are maintained at low concentrations. Excessive transmission leads to excitotoxicity which results in cell damage and death. Glutamatergic dysfunction is involved in many pathologies including neuropsychiatric, neurodegenerative and neurodevelopmental disorders. Impairments in glutamate’s physiological functions, excitotoxicity and disrupted modulation of other neurotranmitter systems contribute to these pathologies. This opinion aims to summarize the cellular mechanism that lead to pathology and review how these mechanisms translate into the clinic.

Association of genetic variants of Glutamate Metabotropic Receptor 5 gene and state-anhedonia

IntroductionAndedonia is one of the core symptoms of depression. It is known that in case of depressed individuals experiencing anhedonia, the classical antidepressants are often ineffective, thus investigation of this symptom would be essential. Recent studies highlight the possible role of the glutamatergic system in anhedonia however, the genetic background of these assumptions is still unclear.ObjectivesOur goal was to investigate the possible associations between state-anhedonia and genetic variants from GRM5 (Glutamate Metabotropic Receptor 5) gene.MethodsFor our analysis we used data from the NewMood (New Molecules in Mood Disorders, LSHM-CT-2004-503474) project. Participants (n = 1820) aged between 18-60, were recruited in Budapest and in Manchester. All volunteers filled out mental-health questionnaires and provided DNA sample. Genotyping was performed by Illumina’s CoreExom PsychChip. Altogether 1282 variants from GRM5 gene survived the genetic quality control steps. State-anhedonia was measured with an item from the Brief Symptom Inventory questionnaire. We performed logistic regression using Plink 2.0. During our analyses, age, gender, population and the top10 principal components of the genome were added into the model as covariates. Correction for linkage-disequilibrium were performed with LDlink.ResultsAfter the correction of linkage-disequilibrium, three independent variables (r2&lt;0.2), (rs1827603, rs6483520, rs35669869) yielded significant (p&lt;0.05) results, both in additive and in dominant model. In case of recessive model, only rs11020880 showed significant (p&lt;0.05) effect.ConclusionsThe detected nominally significant associations between state-anhedonia and genetic variants from GRM5 gene strengthen previous assumptions about the possible relationship between glutamatergic system and anhedonia.DisclosureThis study was supported by: MTA-SE Neuropsychopharmacology and Neurochemistry Research Group; 2017-1.2.1-NKP-2017-00002; KTIA_13_NAPA-II/14; KTIA_NAP_13-1-2013- 0001; KTIA_NAP_13-2- 2015-0001; 2020-4.1.1.-TKP2020 and 2019-2.1.7-ERA-NET-2020-00005 (TRAJEC