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https://www.readbyqxmd.com/read/28645622/in-vivo-effects-of-knocking-down-metabotropic-glutamate-receptor-5-in-the-sod1-g93a-mouse-model-of-amyotrophic-lateral-sclerosis
#1
Tiziana Bonifacino, Luca Cattaneo, Elena Gallia, Aldamaria Puliti, Marcello Melone, Francesca Provenzano, Simone Bossi, Ilaria Musante, Cesare Usai, Fiorenzo Conti, Giambattista Bonanno, Marco Milanese
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to loss of upper and lower motor neurons (MNs). The mechanisms of neuronal death are largely unknown, thus prejudicing the successful pharmacological treatment. One major cause for MN degeneration in ALS is represented by glutamate(Glu)-mediated excitotoxicity. We have previously reported that activation of Group I metabotropic Glu receptors (mGluR1 and mGluR5) at glutamatergic spinal cord nerve terminals produces abnormal Glu release in the widely studied SOD1(G93A) mouse model of ALS...
June 20, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28607044/regulation-of-spinogenesis-in-mature-purkinje-cells-via-mglur-pkc-mediated-phosphorylation-of-camkii%C3%AE
#2
Takeyuki Sugawara, Chihiro Hisatsune, Hiroyuki Miyamoto, Naoko Ogawa, Katsuhiko Mikoshiba
Dendritic spines of Purkinje cells form excitatory synapses with parallel fiber terminals, which are the primary sites for cerebellar synaptic plasticity. Nevertheless, how density and morphology of these spines are properly maintained in mature Purkinje cells is not well understood. Here we show an activity-dependent mechanism that represses excessive spine development in mature Purkinje cells. We found that CaMKIIβ promotes spine formation and elongation in Purkinje cells through its F-actin bundling activity...
June 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28569048/astrocyte-mediated-synapse-remodeling-in-the-pathological-brain
#3
REVIEW
Sun Kwang Kim, Junichi Nabekura, Schuichi Koizumi
Astrocytes, a major type of glia, reciprocally influence synaptic transmission and connectivity, forming the "tripartite synapses". Astrocytic metabotropic glutamate receptor (mGluR)-mediated Ca(2+) waves and release of gliotransmitters or synaptogenic molecules mediate this neuron-glia interaction in the developing brain, but this signaling has been challenged for adult brain. However, cumulative evidence has suggested that mature astrocytes exhibit re-awakening of such immature phenotype in the pathological adult brain...
June 1, 2017: Glia
https://www.readbyqxmd.com/read/28560482/integrated-in-silico-fragment-based-drug-design-case-study-with-allosteric-modulators-on-metabotropic-glutamate-receptor-5
#4
Yuemin Bian, Zhiwei Feng, Peng Yang, Xiang-Qun Xie
GPCR allosteric modulators target at the allosteric binding pockets of G protein-coupled receptors (GPCRs) with indirect influence on the effects of an orthosteric ligand. Such modulators exhibit significant advantages compared to the corresponding orthosteric ligands, including better chemical tractability or physicochemical properties, improved selectivity, and reduced risk of oversensitization towards their receptors. Metabotropic glutamate receptor 5 (mGlu5), a member of class C GPCRs, is a promising therapeutic target for treating many central nervous system diseases...
May 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28555566/activation-of-the-same-mglur5-receptors-in-the-amygdala-causes-divergent-effects-on-specific-versus-indiscriminate-fear
#5
Mohammed Mostafizur Rahman, Sonal Kedia, Giselle Fernandes, Sumantra Chattarji
Although mGluR5-antagonists prevent fear and anxiety, little is known about how the same receptor in the amygdala gives rise to both. Combining in vitro and in vivo activation of mGluR5 in rats, we identify specific changes in intrinsic excitability and synaptic plasticity in basolateral amygdala neurons that give rise to temporally distinct and mutually exclusive effects on fear-related behaviors. The immediate impact of mGluR5 activation is to produce anxiety manifested as indiscriminate fear of both tone and context...
May 30, 2017: ELife
https://www.readbyqxmd.com/read/28554247/association-of-social-defeat-stress-induced-anhedonia-like-symptoms-with-mglur1-dependent-downregulation-of-membrane-ampa-glur1-in-the-mouse-ventral-midbrain
#6
Sayori Yashiro, Kenjiro Seki
Anhedonia is a core symptom of social defeat stress (SDS)-induced depression associated with the reward system. We previously reported that membrane AMPA-GluR1 downregulation in the reward system is associated with lipopolysaccharide-induced anhedonia-like symptoms. Since group I metabotropic glutamate receptor (mGluR) activation reduces the surface density of GluR1, we examined whether group I mGluR-dependent membrane GluR1 downregulation in the reward system is involved in SDS-induced anhedonia-like symptoms...
May 29, 2017: Stress: the International Journal on the Biology of Stress
https://www.readbyqxmd.com/read/28518055/a-positive-feedback-loop-linking-enhanced-mglur-function-and-basal-calcium-in-spinocerebellar-ataxia-type-2
#7
Pratap Meera, Stefan Pulst, Thomas Otis
Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of physiological conditions...
May 18, 2017: ELife
https://www.readbyqxmd.com/read/28503134/aquaporin-4-mediated-glutamate-induced-astrocyte-swelling-is-partially-mediated-through-metabotropic-glutamate-receptor-5-activation
#8
Zhongfang Shi, Wei Zhang, Yang Lu, Yi Lu, Lixin Xu, Qing Fang, Min Wu, Mei Jia, Yujiao Wang, Liping Dong, Xu Yan, Shaohua Yang, Fang Yuan
Astrocytes are one of the most abundant cell types in the mammalian central nervous system (CNS), and astrocyte swelling is the primary event associated with brain edema. Glutamate, the principal excitatory amino acid neurotransmitter in the CNS, is released at high levels after brain injury including cerebral ischemia. This leads to astrocyte swelling, which we previously demonstrated is related to metabotropic glutamate receptor (mGluR) activation. Aquaporin 4 (AQP4), the predominant water channel in the brain, is expressed in astrocyte endfeet and plays an important role in brain edema following ischemia...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28487223/obesogenic-diet-intake-during-pregnancy-programs-aberrant-synaptic-plasticity-and-addiction-like-behavior-to-a-palatable-food-in-offspring
#9
Alberto Camacho, Larisa Montalvo-Martinez, Robbi E Cardenas-Perez, Lizeth Fuentes-Mera, Lourdes Garza-Ocañas
Contextual food conditioned behaviors require plasticity of glutamatergic neurotransmission in the reward system, involving changes in the expression of including a-amino-3-hydroxy-5-methylisoxazole 4-propionate receptors (AMPA), N-methyl-d-aspartic acid (NMDA) and metabotropic glutamate 2,3 (mGlur 2,3). However, the role of changes in glutamatergic synaptic markers on energy-dense palatable food preference during development has not been described. Here, we determine the effect of nutritional programing during gestation on fat food choices using a conditioned place preference (CPP) test and an operant training response and its effect on glutamatergic markers in the nucleus accumbens (Nac) shell and prefrontal cortex (PFC)...
May 6, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28455524/mechanisms-underlying-cognitive-deficits-in-a-mouse-model-for-costello-syndrome-are-distinct-from-other-rasopathy-mouse-models
#10
Jadwiga Schreiber, Laura-Anne Grimbergen, Iris Overwater, Thijs van der Vaart, Jeffrey Stedehouder, Alberto J Schuhmacher, Carmen Guerra, Steven A Kushner, Dick Jaarsma, Ype Elgersma
RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRas (G12V/G12V) mice...
April 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28419871/short-term-inhibition-of-gabaergic-ipscs-induced-by-association-of-pre-and-postsynaptic-activation-in-the-neonatal-hippocampus
#11
Megumi Taketo, Hiroko Matsuda
Activity-dependent plasticity including short and long-term depression accompanied by a reduction in transmitter release probability has been demonstrated in both inhibitory and excitatory synapses. In the neonatal hippocampus, repetitive postsynaptic depolarization is followed by presynaptic alterations of the efficacy of GABAAergic transmission. Both facilitation and inhibition have been observed, but the mechanisms underlying this plasticity have not yet been elucidated. In the present experiment, repetitive postsynaptic depolarization by itself did not cause marked alterations of spontaneous inhibitory postsynaptic currents (sIPSCs)...
April 16, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28417952/investigating-the-molecular-mechanism-of-positive-and-negative-allosteric-modulators-in-the-calcium-sensing-receptor-dimer
#12
Stine Engesgaard Jacobsen, Ulrik Gether, Hans Bräuner-Osborne
Allosteric modulators that are targeting the calcium-sensing receptor (CaSR) hold great therapeutic potential, and elucidating the molecular basis for modulation would thus benefit the development of novel therapeutics. In the present study, we aimed at investigating the mechanism of allosteric modulation in CaSR by testing dimers carrying mutations in the allosteric site of one or both of the subunits. To ensure measurements on a well-defined dimer composition, we applied a trans-activation system in which only the specific heterodimer of two loss-of-function mutants responded to agonist...
April 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28413831/differential-ability-of-the-dorsal-and-ventral-rat-hippocampus-to-exhibit-group-i-metabotropic-glutamate-receptor-dependent-synaptic-and-intrinsic-plasticity
#13
Patrick Tidball, Hannah V Burn, Kai Lun Teh, Arturas Volianskis, Graham L Collingridge, Stephen M Fitzjohn
BACKGROUND: The hippocampus is critically involved in learning and memory processes. Although once considered a relatively homogenous structure, it is now clear that the hippocampus can be divided along its longitudinal axis into functionally distinct domains, responsible for the encoding of different types of memory or behaviour. Although differences in extrinsic connectivity are likely to contribute to this functional differentiation, emerging evidence now suggests that cellular and molecular differences at the level of local hippocampal circuits may also play a role...
January 2017: Brain and neuroscience advances
https://www.readbyqxmd.com/read/28396447/dual-optical-control-and-mechanistic-insights-into-photoswitchable-group-ii-and-iii-metabotropic-glutamate-receptors
#14
Joshua Levitz, Johannes Broichhagen, Philipp Leippe, David Konrad, Dirk Trauner, Ehud Y Isacoff
G protein-coupled receptor (GPCR) signaling occurs in complex spatiotemporal patterns that are difficult to probe using standard pharmacological and genetic approaches. A powerful approach for dissecting GPCRs is to use light-controlled pharmacological agents that are tethered covalently and specifically to genetically engineered receptors. However, deficits in our understanding of the mechanism of such photoswitches have limited application of this approach and its extension to other GPCRs. In this study, we have harnessed the power of bioorthogonal tethering to SNAP and CLIP protein tags to create a family of light-gated metabotropic glutamate receptors (mGluRs)...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28395974/antidepressant-like-activity-of-icariin-mediated-by-group-i-mglurs-in-prenatally-stressed-offspring
#15
Xiaoxiao Zhang, Hongli Sun, Qian Su, Tianwei Lin, Huiping Zhang, Junli Zhang, Shaokang Dang, Zhongliang Zhu
OBJECTIVE: The present study was performed to identify antidepressant-like activity of icariin in prenatally stressed male rats. METHODS: The effects of icariin on PRS-induced depression were examined using sucrose preference test (SPT) and forced swimming test (FST) in male offspring, and measuring protein and mRNA expressions of group I mGluRs receptors and EAAT2 via western blotting and quantitative real-time PCR assays. RESULTS: The results indicated that prenatal restraint stress (PRS) resulted in several behavioral anomalies...
April 7, 2017: Brain & Development
https://www.readbyqxmd.com/read/28393639/the-safety-of-extended-release-drug-formulations-for-the-treatment-of-adhd
#16
REVIEW
Ann Childress
Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder affecting millions of patients worldwide. Effective treatments have been available for more than 60 years in the form of immediate-release (IR) stimulants However, stimulants have a high risk for abuse and are associated with adverse effects Including elevated blood pressure and heart rate, insomnia and decreased appetite. IR formulations also require multiple daily dosing. The search for improved safety, tolerability and convenience has led to the development of multiple extended-release (ER) stimulant and non-stimulant formulations...
May 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28392297/group-ii-metabotropic-glutamate-receptor-interactions-with-nherf-scaffold-proteins-implications-for-receptor-localization-in-brain
#17
Stefanie L Ritter-Makinson, Maryse Paquet, James W Bogenpohl, Rachel E Rodin, C Chris Yun, Edward J Weinman, Yoland Smith, Randy A Hall
The group II metabotropic glutamate receptors mGluR2 and mGluR3 are key modulators of glutamatergic neurotransmission. In order to identify novel Group II metabotropic glutamate receptor (mGluR)-interacting partners, we screened the C-termini of mGluR2 and mGluR3 for interactions with an array of PDZ domains. These screens identified the Na+/H+ exchanger regulatory factors 1 and 2 (NHERF-1 & -2) as candidate interacting partners. Follow-up co-immunoprecipitation studies demonstrated that both mGluR2 and mGluR3 can associate with NHERF-1 and NHERF-2 in a cellular context...
April 7, 2017: Neuroscience
https://www.readbyqxmd.com/read/28369952/a-calcium-dependent-pathway-underlies-activity-dependent-plasticity-of-electrical-synapses-in-the-thalamic-reticular-nucleus
#18
Jessica Sevetson, Sarah Fittro, Emily Heckman, Julie S Haas
Recent results have demonstrated modification of electrical synapse strength by varied forms of neuronal activity. However, the mechanisms underlying plasticity induction in central mammalian neurons are unclear. Here we show that the two established inductors of plasticity at electrical synapses in the thalamic reticular nucleus - paired burst spiking in coupled neurons, and mGluR-dependent tetanization of synaptic input - are separate pathways that converge at a common downstream endpoint. Using occlusion experiments and pharmacology in patched pairs of coupled neurons in vitro, we show that burst-induced depression depends on calcium entry via voltage-gated channels, is blocked by BAPTA chelation, and recruits intracellular calcium release on its way to activation of phosphatase activity...
March 29, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28369311/control-of-glutamate-transport-by-extracellular-potassium-basis-for-a-negative-feedback-on-synaptic-transmission
#19
Theresa S Rimmele, Anne-Bérengère Rocher, Joel Wellbourne-Wood, Jean-Yves Chatton
Glutamate and K+, both released during neuronal firing, need to be tightly regulated to ensure accurate synaptic transmission. Extracellular glutamate and K+ ([K+]o) are rapidly taken up by glutamate transporters and K+-transporters or channels, respectively. Glutamate transport includes the exchange of one glutamate, 3 Na+, and one proton, in exchange for one K+. This K+ efflux allows the glutamate binding site to reorient in the outwardly facing position and start a new transport cycle. Here, we demonstrate the sensitivity of the transport process to [K+]o changes...
June 1, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28365868/metabotropic-glutamate-receptors-protect-oligodendrocytes-from-acute-ischemia-in-the-mouse-optic-nerve
#20
Arthur M Butt, Ilaria Vanzulli, Maria Papanikolaou, Irene Chacon De La Rocha, Virginia E Hawkins
Studies by Bruce Ransom and colleagues have made a major contribution to show that white matter is susceptible to ischemia/hypoxia. White matter contains axons and the glia that support them, notably myelinating oligodendrocytes, which are highly vulnerable to ischemic-hypoxic damage. Previous studies have shown that metabotropic GluRs (mGluRs) are cytoprotective for oligodendrocyte precursor cells and immature oligodendrocytes, but their potential role in adult white matter was unresolved. Here, we report that group 1 mGluR1/5 and group 2 mGluR3 subunits are expressed in optic nerves from mice aged postnatal day (P)8-12 and P30-35...
April 1, 2017: Neurochemical Research
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