Modulation of circuit oscillations in the rat anterior cingulate cortex (ACC) in vitro by mGlu2 metabotropic glutamate receptors and alleviation of the effects of phencyclidine-induced NMDA-receptor hypofunction.

Aberrant cortical oscillations in the beta and gamma range are associated with symptoms of schizophrenia and other psychiatric conditions. We have thus investigated the ability of anterior cingulate cortex (ACC) in vitro to generate beta and gamma oscillations, and how these are affected by Group II metabotropic glutamate (mGlu) receptor activation and blockade of N-methyl-d-aspartate (NMDA) receptors. Activation of Group II mGlu receptors, and mGlu2 specifically, with orthosteric agonists reduced the power of both beta and gamma oscillations in ACC without a significant effect on oscillation peak frequencies.

The role of thalamic group II mGlu receptors in health and disease.

The thalamus plays a pivotal role in the integration and processing of sensory, motor, and cognitive information. It is therefore important to understand how the thalamus operates in states of both health and disease. In the present review, we discuss the function of the Group II metabotropic glutamate (mGlu) receptors within thalamic circuitry, and how they may represent therapeutic targets in treating disease states associated with thalamic dysfunction.

Group II metabotropic glutamate receptor (mGlu and mGlu ) roles in thalamic processing.

Background And Purpose: As the thalamus underpins almost all aspects of behaviour, it is important to understand how the thalamus operates. Group II metabotropic glutamate (mGlu /mGlu ) receptor activation reduces inhibition in thalamic nuclei originating from the surrounding thalamic reticular nucleus (TRN). Whilst an mGlu component to this effect has been reported, in this study, we demonstrate that it is likely, largely mediated via mGlu .

Receptor variants and the development of centrally acting medications .

The progressive changes in research paradigms observed in the largest pharmaceutical companies and the burgeoning of biotechnology startups over the last 10 years have generated a need for outsourcing research facilities. In parallel, progress made in the fields of genomics, protein expression in recombinant systems, and electrophysiological recording methods have offered new possibilities for the development of contract research organizations (CROs). Successful partnering between pharmaceutical companies and CROs largely depends upon the competences and scientific quality on offer for the discovery of novel active molecules and targets.

Improving mitochondrial function significantly reduces metabolic, visual, motor and cognitive decline in aged Drosophila melanogaster.

Mitochondria play a major role in aging. Over time, mutations accumulate in mitochondrial DNA leading to reduced adenosine triphosphate (ATP) production and increased production of damaging reactive oxygen species. If cells fail to cope, they die.

Improving Mitochondrial Function Protects Bumblebees from Neonicotinoid Pesticides.

Global pollination is threatened by declining insect pollinator populations that may be linked to neonicotinoid pesticide use. Neonicotinoids over stimulate neurons and depolarize their mitochondria, producing immobility and death. However, mitochondrial function can be improved by near infrared light absorbed by cytochrome c oxidase in mitochondrial respiration.

P2XR modulation of visually evoked synaptic responses in the retina.

P2XRs are distributed throughout all layers of the retina, and thus, their localisation on various cell types puts into question their specific site(s) of action. Using a dark-adapted, ex vivo mouse retinal whole mount preparation, the present study aimed to characterise the effect of P2XR activation on light-evoked, excitatory RGC ON-field excitatory post-synaptic potentials (fEPSPs) and on outer retinal electroretinogram (ERG) responses under comparable conditions. The pharmacologically isolated NMDA receptor-mediated RGC ON-fEPSP was reduced in the presence of BzATP, an effect which was significantly attenuated by A438079 and other selective P2XR antagonists A804598 or AF27139.

Cinnabarinic acid and xanthurenic acid: Two kynurenine metabolites that interact with metabotropic glutamate receptors.

Cinnabarinic and xanthurenic acids are kynurenine metabolites generated by oxidative dimerization of 3-hydroxyanthranilic acid and transamination of 3-hydroxykynurenine, respectively. Recent evidence suggests that both compounds can affect brain function and neurotransmission and interact with metabotropic glutamate (mGlu) receptors. Cinnabarinic acid behaves as an orthosteric agonist of mGlu4 receptors, whereas some of the in vitro and in vivo effects produced by xanthurenic acid appear to be mediated by the activation of mGlu2 and mGlu3 receptors.

Editorial (Thematic Selection: Special Issue on Metabotropic Glutamate Receptors).

The selection of articles in this special issue was solicited following the highly successful , held in Taormina (Italy) in October 2014, and organised under the chairmanship of Professor Ferdinando Nicoletti. All papers were written and submitted after the conclusion of the meeting and were independently peer-reviewed. As always, we are grateful to those experts who have given their time to review the papers.

Figure-ground modulation in awake primate thalamus.

Figure-ground discrimination refers to the perception of an object, the figure, against a nondescript background. Neural mechanisms of figure-ground detection have been associated with feedback interactions between higher centers and primary visual cortex and have been held to index the effect of global analysis on local feature encoding. Here, in recordings from visual thalamus of alert primates, we demonstrate a robust enhancement of neuronal firing when the figure, as opposed to the ground, component of a motion-defined figure-ground stimulus is located over the receptive field.

Near-infrared light increases ATP, extends lifespan and improves mobility in aged Drosophila melanogaster.

Ageing is an irreversible cellular decline partly driven by failing mitochondrial integrity. Mitochondria accumulate DNA mutations and reduce ATP production necessary for cellular metabolism. This is associated with inflammation.

Purines in the eye: recent evidence for the physiological and pathological role of purines in the RPE, retinal neurons, astrocytes, Müller cells, lens, trabecular meshwork, cornea and lacrimal gland.

This review highlights recent findings that describ how purines modulate the physiological and pathophysiological responses of ocular tissues. For example, in lacrimal glands the cross-talk between P2X7 receptors and both M3 muscarinic receptors and α1D-adrenergic receptors can influence tear secretion. In the cornea, purines lead to post-translational modification of EGFR and structural proteins that participate in wound repair in the epithelium and influence the expression of matrix proteins in the stroma.

Dendritic changes in rat visual pathway associated with experimental ocular hypertension.

Purpose: Increasing evidence shows that structural changes in dendrites play an important role in neuronal degenerative processes. The aims of this study were to characterize and delineate morphological changes of dendrites in retinal ganglion cells (RGCs) and their central target neurons in the superior colliculus (SC) and lateral geniculate nucleus (LGN) in experimental rat glaucoma.

Methods: Chronic ocular hypertension (OHT) was surgically induced in rats and animals were sacrificed at 1, 4, 8, 16 and 32 weeks following IOP elevation.

Recharging mitochondrial batteries in old eyes. Near infra-red increases ATP.

Progressive accumulation of age related mitochondrial DNA mutations reduce ATP production and increase reactive oxygen species output, leading to oxidative stress, inflammation and degradation. The pace of this is linked to metabolic demand. The retina has the greatest metabolic demand and mitochondrial density in the body and displays progressive age related inflammation and marked cell loss.

Electroretinogram and visual-evoked potential assessment of retinal and central visual function in a rat ocular hypertension model of glaucoma.

Purpose/aim: The aim of the study was to investigate the long-term functional changes that may occur in the retina and visual cortex in a rat ocular hypertension (OHT) model of glaucoma, used in our lab for treatment studies, using electroretinogram (ERG) and visual-evoked potential (VEP) cortical recordings in order to test the hypothesis that experimental glaucoma has differential retinal and central effects.

Materials And Methods: Experimental glaucoma was induced unilaterally in Dark Agouti rats using hypertonic saline injection into the episcleral veins. After 3, 8, 16 and 26 weeks, ERGs and VEPs were recorded under scotopic conditions using brief full-field white flashes (10 μcd s m(-2) to 10.

ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: in vitro and in vivo characterization.

Metabotropic glutamate receptor 7 (mGlu(7)) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu(7) negative allosteric modulator (NAM) (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743). In vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(+)-2-amino-4-phosphonobutyric acid-induced synaptic depression confirmed activity at the native receptor.

Human Müller glia with stem cell characteristics differentiate into retinal ganglion cell (RGC) precursors in vitro and partially restore RGC function in vivo following transplantation.

Müller glia with stem cell characteristics have been identified in the adult human eye, and although there is no evidence that they regenerate retina in vivo, they can be induced to grow and differentiate into retinal neurons in vitro. We differentiated human Müller stem cells into retinal ganglion cell (RGC) precursors by stimulation with fibroblast growth factor 2 together with NOTCH inhibition using the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). Differentiation into RGC precursors was confirmed by gene and protein expression analysis, changes in cytosolic [Ca(2+)] in response to neurotransmitters, and green fluorescent protein (GFP) expression by cells transduced with a transcriptional BRN3b-GFP reporter vector.

Differential feedback modulation of center and surround mechanisms in parvocellular cells in the visual thalamus.

Many cells in both the central visual system and other sensory systems exhibit a center surround organization in their receptive field, where the response to a centrally placed stimulus is modified when a surrounding area is also stimulated. This can follow from laterally directed connections in the local circuit at the level of the cell in question but could also involve more complex interactions. In the lateral geniculate nucleus (LGN), the cells relaying the retinal input display a concentric, center surround organization that in part follows from the similar organization characterizing the retinal cells providing their input.

Changes in the modulation of retinocollicular transmission through group III mGluRs long after an increase in intraocular pressure in a rat model of glaucoma.

Metabotropic glutamate receptors (mGluRs) have been shown to be involved in the modulation of retinocollicular neurotransmission. In glaucoma, retinal ganglion cells (RGCs) degenerate, which may have an implication on this transmission as the superior colliculus is their major central target in the much-used rodent models of the disease. We have investigated this using an in vitro slice preparation of the superior colliculus by eliciting field excitatory postsynaptic potentials (fEPSPs) through optic tract stimulation in a rat ocular hypertension model of glaucoma.

Metabotropic glutamate receptors in the thalamocortical network: strategic targets for the treatment of absence epilepsy.

Metabotropic glutamate (mGlu) receptors are positioned at synapses of the thalamocortical network that underlie the development of spike-and-wave discharges (SWDs) associated with absence epilepsy. The modulatory role of individual mGlu receptor subtypes on excitatory and inhibitory synaptic transmission in the cortico-thalamo-cortical circuitry makes subtype-selective mGlu receptor ligands potential candidates as novel antiabsence drugs. Some of these compounds are under clinical development for the treatment of numerous neurologic and psychiatric disorders, and might be soon available for clinical studies in patients with absence seizures refractory to conventional medications.

Dendritic changes in visual pathways in glaucoma and other neurodegenerative conditions.

Visual information is sent from the retina to central visual targets through the optic nerve formed of retinal ganglion cells' (RGCs) axons. In rodents, the superior colliculus (SC) is the major site of termination of retinal axons, whilst in primates and felines, it is the lateral geniculate nucleus (LGN). Glaucoma is a progressive optic neuropathy characterized by RGC death.

Neuroprotection in glaucoma - Is there a future role?

In glaucoma, the major cause of global irreversible blindness, there is an urgent need for treatment modalities that directly target the RGCs. The discovery of an alternative therapeutic approach, independent of IOP reduction, is highly sought after, due to the indirect nature and limited effectiveness of IOP lowering therapy in preventing RGC loss. Several mechanisms have been implicated in initiating the apoptotic cascade in glaucomatous retinopathy and numerous drugs have been shown to be neuroprotective in animal models of glaucoma.