A role for Seven in Absentia Homolog (Siah1a) in metabotropic glutamate receptor signaling

Background  

The mammalian homologue of Seven in Absentia (Siah) can act in the ubiquitin/proteasome pathway. Recent work has shown that Siah can bind group I metabotropic glutamate receptors (mGluRs), but the functional consequences of this interaction are unknown.     

Uptake of 3H-cAMP by retinal pigment epithelium isolated from bluegill sunfish (Lepomis macrochirus)

Background  

Metabotropic glutamate receptors (mGluRs) regulate neuronal excitability and synaptic strength. The group I mGluRs, mGluR1 and 5, are widespread in the brain and localize to post-synaptic sites. The Homer protein family regulates group I mGluR function and distribution. Constitutively expressed 'long' Homer proteins (Homer 1b, 1c, 2 and 3) induce dendritic localization of group I mGluRs and receptor clustering, either internally or on the plasma membrane. Short Homer proteins (Homer 1a, Ania-3) exhibit regulated expression and act as dominant negatives, producing effects on mGluR distribution and function that oppose those of the long Homer proteins.     

Effects of the group I metabotropic glutamate receptor agonist,DHPG, and injection stress on striatal cell signaling in food-restricted and ad libitum fed rats

Background  

Chronic food restriction augments the rewarding effect of centrally administered psychostimulant drugs and this effect may involve a previously documented upregulation of D-1 dopamine receptor-mediated MAP kinase signaling in nucleus accumbens (NAc) and caudate-putamen (CPu). Psychostimulants are known to induce striatal glutamate release, and group I metabotropic glutamate receptors (mGluR) have been implicated in the cellular and behavioral responses to amphetamine. The purpose of the present study was to evaluate whether chronic food restriction increases striatal MAP kinase signaling in response to the group I mGluR agonist, DHPG.     

Genomic responses in rat cerebral cortex after traumatic brain injury

Background  

Traumatic brain injury (TBI) initiates a complex sequence of destructive and neuroprotective cellular responses. The initial mechanical injury is followed by an extended time period of secondary brain damage. Due to the complicated pathological picture a better understanding of the molecular events occurring during this secondary phase of injury is needed. This study was aimed at analysing gene expression patterns following cerebral cortical contusion in rat using high throughput microarray technology with the goal of identifying genes involved in an early and in a more delayed phase of trauma, as genomic responses behind secondary mechanisms likely are time-dependent.     

Metabolite differences between glutamate carboxypeptidase II gene knockout mice and their wild-type littermates after traumatic brain injury: a 7-tesla <Superscript>1</Superscript>H-MRS study

Background

Traumatic brain injury (TBI) is a complex condition and remains a prominent public and medical health issue in individuals of all ages. A rapid increase in extracellular glutamate occurs after TBI, leading to glutamate-induced excitotoxicity, which causes neuronal damage and further functional impairments. Although inhibition of glutamate carboxypeptidase II (GCP II) is considered a potential approach for reducing glutamate-induced excitotoxicity after TBI, further detailed evidence regarding its efficacy is required. Therefore, in this study, we examined the differences in the metabolite status between wild-type (WT) and GCP II gene-knockout (KO) mice after TBI using proton magnetic resonance spectroscopy (1H-MRS) and T2-weighted magnetic resonance (MR) imaging with a 7-tesla imaging system, and brain water-content analysis.

Results

Evaluation of glutamate and N-acetylaspartate concentrations revealed a decrease in both levels in the ipsilateral hippocampus at 24 h post-TBI; however, the reduction in glutamate and N-acetylaspartate levels was less marked in GCP II-KO mice than in WT mice (p?<?0.05). T2 MR data and brain water-content analysis demonstrated that the extent of cortical edema and brain swelling was less in KO than in WT mice after TBI (p?<?0.05).

Conclusion

Using two non-invasive methods, 1H-MRS and T2 MR imaging, as well as in vitro brain-water content measurements, we demonstrated that the mechanism underlying the neuroprotective effects of GCP II-KO against brain swelling in TBI involves changes in glutamate and N-acetylaspartate levels. This knowledge may contribute towards the development of therapeutic strategies for TBI.

     

Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway

Background  

MEK1/2 is a serine/threonine protein that phosphorylates extracellular signal-regulated kinase (ERK1/2). Cerebral ischemia results in enhanced expression of cerebrovascular contractile receptors in the middle cerebral artery (MCA) leading to the ischemic region. Here we explored the role of the MEK/ERK pathway in receptor expression following ischemic brain injury using the specific MEK1 inhibitor U0126.     

Proliferation dynamics of germinative zone cells in the intact and excitotoxically lesioned postnatal rat brain

Background  

The forebrain subventricular zone (SVZ)-olfactory bulb pathway and hippocampal subgranular zone (SGZ) generate neurons into adulthood in the mammalian brain. Neurogenesis increases after injury to the adult brain, but few studies examine the effect of injury on neural and glial precursors in the postnatal brain. To characterize the spatio-temporal dynamics of cell proliferation in the germinative zones, this study utilized a model of postnatal damage induced by NMDA injection in the right sensorimotor cortex at postnatal day 9.     

Expression of ionotropic glutamate receptors in the retina of the rdta transgenic mouse

Background  

The expression of retinal CaMKII is up-regulated in the retina of the rdta mouse in which rod photoreceptors are genetically ablated. As ionotropic glutamate receptors are known substrates of CAMKII, this study set out to determine if the protein levels of ionotropic glutamate receptors in the rdta mouse retina are also affected.     

The neuroblast and angioblast chemotaxic factor SDF-1 (CXCL12) expression is briefly up regulated by reactive astrocytes in brain following neonatal hypoxic-ischemic injury

Background  

Stromal cell-derived factor 1 (SDF-1 or CXCL12) is chemotaxic for CXCR4 expressing bone marrow-derived cells. It functions in brain embryonic development and in response to ischemic injury in helping guide neuroblast migration and vasculogenesis. In experimental adult stroke models SDF-1 is expressed perivascularly in the injured region up to 30 days after the injury, suggesting it could be a therapeutic target for tissue repair strategies. We hypothesized that SDF-1 would be expressed in similar temporal and spatial patterns following hypoxic-ischemic (HI) injury in neonatal brain.     

Evidence for a role of glutamate as an efferent transmitter in taste buds

Background  

Glutamate has been proposed as a transmitter in the peripheral taste system in addition to its well-documented role as an umami taste stimulus. Evidence for a role as a transmitter includes the presence of ionotropic glutamate receptors in nerve fibers and taste cells, as well as the expression of the glutamate transporter GLAST in Type I taste cells. However, the source and targets of glutamate in lingual tissue are unclear. In the present study, we used molecular, physiological and immunohistochemical methods to investigate the origin of glutamate as well as the targeted receptors in taste buds.     

Functional distribution of Ca<Superscript>2+</Superscript>-coupled P2 purinergic receptors among adrenergic and noradrenergic bovine adrenal chromaffin cells

Background  

Adrenal chromaffin cells mediate acute responses to stress through the release of epinephrine. Chromaffin cell function is regulated by several receptors, present both in adrenergic (AD) and noradrenergic (NA) cells. Extracellular ATP exerts excitatory and inhibitory actions on chromaffin cells via ionotropic (P2X) and metabotropic (P2Y) receptors. We have taken advantage of the actions of the purinergic agonists ATP and UTP on cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) to determine whether P2X and P2Y receptors might be asymmetrically distributed among AD and NA chromaffin cells.     

Regulation of glutamatergic signalling by PACAP in the mammalian suprachiasmatic nucleus

Background  

Previous studies indicate that light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells that contain both glutamate and pituitary adenylyl cyclase activating peptide (PACAP). While the role of glutamate in this pathway has been well studied, the involvement of PACAP and its receptors are only beginning to be understood. Speculating that PACAP may function to modulate how neurons in the suprachiasmatic nucleus respond to glutamate, we used electrophysiological and calcium imaging tools to examine possible cellular interactions between these co-transmitters.     

Blockade of NMDA receptor subtype NR2B prevents seizures but not apoptosis of dentate gyrus neurons in bacterial meningitis in infant rats

Background

Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (RO 25-6981). Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28) or 3.75 mg (150 mg/kg; n = 15) every 3 h or an equal volume of sterile saline (250 μl; n = 40) starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus.

Results

Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P < 0.05 for all RO 25-6981 treated animals combined). The extent of apoptosis was not affected by low or high doses of RO 25-6981. Number of apoptotic cells (median [range]) was 12.76 [3.16–25.3] in animals treated with low dose RO 25-6981 (control animals 13.8 [2.60–31.8]; (P = NS) and 9.8 [1.7–27.3] (controls: 10.5 [2.4–21.75]) in animals treated with high dose RO 25-6981 (P = NS).

Conclusions

Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures.

     

Expression of Galpha14 in sweet-transducing taste cells of the posterior tongue

Background  

"Type II"/Receptor cells express G protein-coupled receptors (GPCRs) for sweet, umami (T1Rs and mGluRs) or bitter (T2Rs), as well as the proteins for downstream signalling cascades. Transduction downstream of T1Rs and T2Rs relies on G-protein and PLCβ2-mediated release of stored Ca²⁺. Whereas Gαgus (gustducin) couples to the T2R (bitter) receptors, which Gα-subunit couples to the sweet (T1R2 + T1R3) receptor is presently not known. We utilized RT-PCR, immunocytochemistry and single-cell gene expression profiling to examine the expression of the Gαq family (q, 11, 14) in mouse taste buds.     

Effect of neutrophil depletion on gelatinase expression,edema formation and hemorrhagic transformation after focal ischemic stroke

Background  

While gelatinase (MMP-2 and -9) activity is increased after focal ischemia/reperfusion injury in the brain, the relative contribution of neutrophils to the MMP activity and to the development of hemorrhagic transformation remains unknown.     

Response of regional brain glutamate transaminases of rat to aluminum in protein malnutrition

Background  

The mechanism of aluminum-induced neurotoxicity is not clear. The involvement of glutamate in the aluminium-induced neurocomplications has been suggested. Brain glutamate levels also found to be altered in protein malnutrition. Alterations in glutamate levels as well as glutamate-α-decarboxylase in different regions of rat brain has been reported in response to aluminum exposure. Thus the study of glutamate metabolising enzymes in different brain regions of rats maintained on either normal or restricted protein diet may be of importance for understanding the neurotoxicity properties of aluminium.     

Interaction of Cupidin/Homer2 with two actin cytoskeletal regulators, Cdc42 small GTPase and Drebrin, in dendritic spines

Background  

Homer is a postsynaptic scaffold protein that links various synaptic signaling proteins, including the type I metabotropic glutamate receptor subunits 1α and 5, the inositol 1,4,5-trisphosphate receptor, Shank and Cdc42 small GTPase. Overexpression of Homer induces changes in dendritic spine morphology in cultured hippocampal neurons. However, the molecular basis underpinning Homer-mediated spine morphogenesis remains unclear. In this study, we aimed to elucidate the structural and functional properties of the interaction between Cupidin/Homer2 and two actin-cytoskeletal regulators, Cdc42 small GTPase and Drebrin.     

Isoflurane depresses hippocampal CA1 glutamate nerve terminals without inhibiting fiber volleys

Background  

Anesthetic-induced CNS depression is thought to involve reduction of glutamate release from nerve terminals. Recent studies suggest that isoflurane reduces glutamate release by block of Na channels. To further investigate this question we examined the actions of isoflurane, TTX, extracellular Ca²⁺, CNQX and stimulus voltage (stim) on glutamate-mediated transmission at hippocampal excitatory synapses. EPSPs were recorded from CA1 neurons in rat hippocampal brain slices in response to Schaffer-collateral fiber stimulation.     

Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke

Background  

Matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) are increased in the brain after experimental ischemic stroke in rats. These two proteases are involved with the degradation of the basal lamina and loss of stability of the blood brain barrier that occurs after ischemia and that is associated with thrombolytic therapy in ischemic stroke. Minocycline is a lipophilic tetracycline and is neuroprotective in several models of brain injury. Minocycline inhibits inflammation, apoptosis and extracellular matrix degradation. In this study we investigated whether delayed minocycline inhibits brain MMPs activated by ischemia in a model of temporary occlusion in Wistar rats.