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1.
J Neurosci ; 35(34): 11960-75, 2015 Aug 26.
Article in English | MEDLINE | ID: mdl-26311777

ABSTRACT

Within the hippocampus, the major somatostatin (SRIF) receptor subtype, the sst2A receptor, is localized at postsynaptic sites of the principal neurons where it modulates neuronal activity. Following agonist exposure, this receptor rapidly internalizes and recycles slowly through the trans-Golgi network. In epilepsy, a high and chronic release of somatostatin occurs, which provokes, in both rat and human tissue, a decrease in the density of this inhibitory receptor at the cell surface. The insulin-regulated aminopeptidase (IRAP) is involved in vesicular trafficking and shares common regional distribution with the sst2A receptor. In addition, IRAP ligands display anticonvulsive properties. We therefore sought to assess by in vitro and in vivo experiments in hippocampal rat tissue whether IRAP ligands could regulate the trafficking of the sst2A receptor and, consequently, modulate limbic seizures. Using pharmacological and cell biological approaches, we demonstrate that IRAP ligands accelerate the recycling of the sst2A receptor that has internalized in neurons in vitro or in vivo. Most importantly, because IRAP ligands increase the density of this inhibitory receptor at the plasma membrane, they also potentiate the neuropeptide SRIF inhibitory effects on seizure activity. Our results further demonstrate that IRAP is a therapeutic target for the treatment of limbic seizures and possibly for other neurological conditions in which downregulation of G-protein-coupled receptors occurs. SIGNIFICANCE STATEMENT: The somatostatin type 2A receptor (sst2A) is localized on principal hippocampal neurons and displays anticonvulsant properties. Following agonist exposure, however, this receptor rapidly internalizes and recycles slowly. The insulin-regulated aminopeptidase (IRAP) is involved in vesicular trafficking and shares common regional distribution with the sst2A receptor. We therefore assessed by in vitro and in vivo experiments whether IRAP could regulate the trafficking of this receptor. We demonstrate that IRAP ligands accelerate sst2A recycling in hippocampal neurons. Because IRAP ligands increase the density of sst2A receptors at the plasma membrane, they also potentiate the effects of this inhibitory receptor on seizure activity. Our results further demonstrate that IRAP is a therapeutic target for the treatment of limbic seizures.


Subject(s)
Cystinyl Aminopeptidase/metabolism , Hippocampus/metabolism , Receptors, Somatostatin/metabolism , Seizures/metabolism , Seizures/prevention & control , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Limbic System/metabolism , Male , Mice , Protein Transport/physiology , Rats , Rats, Wistar
2.
Epilepsy Behav ; 46: 66-71, 2015 May.
Article in English | MEDLINE | ID: mdl-25922088

ABSTRACT

In the management of epilepsy, AT1 receptor antagonists have been suggested as an additional treatment strategy. A hyperactive brain angiotensin (Ang) II system and upregulated AT1 receptors are implicated in the cerebrovascular alterations in a genetic form of hypertension. Uncontrolled hypertension could also, in turn, be a risk factor for a seizure threshold decrease and development of epileptogenesis. The present study aimed to assess the effects of the selective AT1 receptor antagonist ZD7155 on kainic acid (KA)-induced status epilepticus (SE) development and accompanying changes in the hippocampal extracellular (EC) neurotransmitter levels of noradrenaline (NAD), serotonin (5-HT), and dopamine (DA) in spontaneously hypertensive rats (SHRs) and their parent strain Wistar-Kyoto (WKY) rats, since monoamines are well-known neurotransmitters involved in mechanisms of both epilepsy and hypertension. Status epilepticus was evoked in freely moving rats by a repetitive intraperitoneal (i.p.) administration of KA in subconvulsant doses. In the treatment group, ZD7155 (5mg/kg i.p.) was coadministered with the first KA injection. Spontaneously hypertensive rats exhibited higher susceptibility to SE than WKY rats, but the AT1 receptor antagonist did not alter the development of SE in SHRs or in WKY rats. In vivo microdialysis demonstrated significant KA-induced increases of the hippocampal NAD and DA levels in SHRs and of NAD, 5-HT, and DA in WKY rats. Although SHRs developed more severe seizures while receiving a lower dose of KA compared to WKY rats, AT1 receptor antagonism completely prevented all KA-induced increases of hippocampal monoamine levels in both rat strains without affecting seizure development per se. These results suggest a lack of direct relationship between KA-induced seizure susceptibility and adaptive changes of hippocampal NAD, 5-HT, and DA levels in the effects of ZD7155 in WKY rats and SHRs.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Dopamine/metabolism , Hippocampus/metabolism , Naphthyridines/pharmacology , Norepinephrine/metabolism , Serotonin/metabolism , Status Epilepticus/drug therapy , Animals , Disease Models, Animal , Excitatory Amino Acid Agonists/pharmacology , Hippocampus/drug effects , Kainic Acid/pharmacology , Male , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Status Epilepticus/chemically induced
3.
Nutr Neurosci ; 16(2): 78-82, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23324588

ABSTRACT

L-Theanine, an ethylamide derivate of glutamate found in abundance in green tea, has been shown to exert beneficial actions in animal models for several neurological disorders. We here investigated for the first time the effect of L-theanine intake on seizure susceptibility using acute pilocarpine and pentylenetetrazol (PTZ) mouse models for studying, respectively, limbic seizures or primarily generalized seizures. Moreover, we studied the effect of l-theanine intake on extracellular hippocampal and cortical glutamate and gamma-aminobutyric acid (GABA) levels, using in vivo microdialysis. Feeding mice with a 4% L-theanine solution significantly decreased their susceptibility to pilocarpine-induced seizures whereas susceptibility to PTZ-induced seizures was increased. The latter effect was linked to decreased extracellular GABA concentrations in frontal cortex.


Subject(s)
Glutamates/pharmacology , Seizures/drug therapy , gamma-Aminobutyric Acid/metabolism , Animals , Disease Models, Animal , GABA Agents/metabolism , Glutamates/administration & dosage , Glutamic Acid/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Male , Mice , Mice, Inbred Strains , Microdialysis , Pentylenetetrazole/adverse effects , Pilocarpine/adverse effects , Seizures/chemically induced , Tea/chemistry
4.
Int J Neuropsychopharmacol ; 16(5): 1153-63, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23177092

ABSTRACT

Oxytocin is a neuromodulator with antidepressant-like effects. In vitro, oxytocin is rapidly cleaved by insulin-regulated aminopeptidase (IRAP). Oxytocin metabolites are known to exert strong central activities that are different from the effects of the parent molecule. Our goal is to investigate in vivo whether IRAP deletion modifies the antidepressant-like effects of oxytocin. Male and female C57Bl/6 mice, IRAP wild-type (IRAP(+/+)) and knock-out (IRAP(-/-)) mice were injected subcutaneously with saline, oxytocin or oxytocin combined with angiotensin IV. One hour after injection, immobility was timed during a 5 min forced swim that was preceded by an open field to study locomotor behaviour. Oxytocin induced antidepressant-like effects in male (0.25 mg/kg oxytocin) and female (0.15 mg/kg oxytocin) C57Bl/6 mice subjected to the forced swim test. Oxytocin did not influence locomotor behaviour in mice, as shown with the open field. These findings were reproduced in transgenic male (aged 3-6 months) and female (aged 12-18 months) IRAP(+/+) mice. However, the major findings of our study were that the antidepressant-like effect was reversed in angiotensin IV treated IRAP(+/+) mice and was completely absent in age- and gender-matched IRAP(-/-) mice. The lack of an antidepressant-like effect of oxytocin in young male and middle-aged female IRAP(-/-) mice attributes an important role to IRAP in mediating this effect.


Subject(s)
Aminopeptidases/metabolism , Antidepressive Agents/therapeutic use , Depression/drug therapy , Oxytocin/therapeutic use , Age Factors , Angiotensin II/analogs & derivatives , Angiotensin II/pharmacology , Animals , Antidepressive Agents/pharmacology , Cell Membrane/drug effects , Cell Membrane/enzymology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cystinyl Aminopeptidase/deficiency , Cystinyl Aminopeptidase/genetics , Depression/blood , Depression/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Female , Imipramine/therapeutic use , Immobility Response, Tonic/drug effects , Insulin/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Oxytocin/blood , Oxytocin/pharmacology
5.
Neurotherapeutics ; 9(3): 658-72, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22669710

ABSTRACT

Ghrelin is a pleiotropic neuropeptide that has been recently implicated in epilepsy. Animal studies performed to date indicate that ghrelin has anticonvulsant properties; however, its mechanism of anticonvulsant action is unknown. Here we show that the anticonvulsant effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR). To our surprise, however, we found that the GHSR knockout mice had a higher seizure threshold than their wild-type littermates when treated with pilocarpine. Using both in vivo and in vitro models, we further discovered that inverse agonism and desensitization/internalization of the GHSR attenuate limbic seizures in rats and epileptiform activity in hippocampal slices. This constitutes a novel mechanism of anticonvulsant action, whereby an endogenous agonist reduces the activity of a constitutively active receptor.


Subject(s)
Anticonvulsants/therapeutic use , Ghrelin/therapeutic use , Limbic System/drug effects , Receptors, Ghrelin/metabolism , Seizures/drug therapy , Seizures/pathology , Analysis of Variance , Animals , Anticonvulsants/pharmacology , Calcium/metabolism , Disease Models, Animal , Disease Susceptibility , Dose-Response Relationship, Drug , Drug Interactions , Electric Stimulation , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/genetics , Green Fluorescent Proteins/genetics , HEK293 Cells , Hippocampus/cytology , Humans , In Vitro Techniques , Limbic System/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microdialysis , Muscarinic Agonists/toxicity , Neurons/drug effects , Patch-Clamp Techniques , Pilocarpine/toxicity , Piperidines/therapeutic use , Pyrazoles/therapeutic use , Rats , Rats, Wistar , Receptors, Ghrelin/agonists , Receptors, Ghrelin/deficiency , Seizures/genetics , Severity of Illness Index , Species Specificity , Transfection , gamma-Aminobutyric Acid/metabolism
6.
Epilepsy Behav ; 22(3): 450-60, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21962757

ABSTRACT

In the past, antidepressants have been thought to possess proconvulsant properties. This assumption remains controversial, however, because anticonvulsant effects have been attributed to certain antidepressants. To date, it remains unclear which antidepressants can be used for the treatment of patients with epilepsy with depression. The present study was designed to determine the anticonvulsant and/or proconvulsant effects of three antidepressants (citalopram, reboxetine, bupropion) against pilocarpine- and pentylenetetrazole-induced acute seizures in larval zebrafish and mice. In zebrafish, all antidepressants were anticonvulsant in the pentylenetetrazole model. In addition, citalopram was anticonvulsant in the zebrafish pilocarpine model, whereas reboxetine and bupropion were without significant effect. In mice all three antidepressants increased some thresholds for pentylenetetrazole-induced convulsive-like behaviors at varying doses, whereas thresholds for pilocarpine-induced convulsive-like behaviors were generally lowered, particularly at the highest doses tested. In general we conclude that the convulsant liability of antidepressants is model and concentration dependent.


Subject(s)
Antidepressive Agents/therapeutic use , Convulsants/toxicity , Seizures/chemically induced , Seizures/drug therapy , Analysis of Variance , Animals , Animals, Genetically Modified , Behavior, Animal/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Green Fluorescent Proteins/genetics , Male , Mice , Pentylenetetrazole/toxicity , Pilocarpine/toxicity , Seizures/mortality , Seizures/physiopathology , Zebrafish
7.
Proc Natl Acad Sci U S A ; 108(33): 13782-7, 2011 Aug 16.
Article in English | MEDLINE | ID: mdl-21804034

ABSTRACT

NMDA type glutamate receptors (NMDARs) are best known for their role in synaptogenesis and synaptic plasticity. Much less is known about their developmental role before neurons form synapses. We report here that VEGF, which promotes migration of granule cells (GCs) during postnatal cerebellar development, enhances NMDAR-mediated currents and Ca(2+) influx in immature GCs before synapse formation. The VEGF receptor Flk1 forms a complex with the NMDAR subunits NR1 and NR2B. In response to VEGF, the number of Flk1/NR2B coclusters on the cell surface increases. Stimulation of Flk1 by VEGF activates Src-family kinases, which increases tyrosine phosphorylation of NR2B. Inhibition of Src-family kinases abolishes the VEGF-dependent NR2B phosphorylation and amplification of NMDAR-mediated currents and Ca(2+) influx in GCs. These findings identify VEGF as a modulator of NMDARs before synapse formation and highlight a link between an activity-independent neurovascular guidance cue (VEGF) and an activity-regulated neurotransmitter receptor (NMDAR).


Subject(s)
Cerebellum/cytology , Neurons/ultrastructure , Receptors, N-Methyl-D-Aspartate/physiology , Vascular Endothelial Growth Factor A/physiology , src-Family Kinases/metabolism , Angiogenesis Inducing Agents , Animals , Calcium/metabolism , Mice , Multiprotein Complexes , Phosphorylation , Receptors, Neurotransmitter , Synapses , Vascular Endothelial Growth Factor Receptor-2/metabolism
8.
J Neurosci ; 31(15): 5792-803, 2011 Apr 13.
Article in English | MEDLINE | ID: mdl-21490221

ABSTRACT

System x(c)- exchanges intracellular glutamate for extracellular cystine, giving it a potential role in intracellular glutathione synthesis and nonvesicular glutamate release. We report that mice lacking the specific xCT subunit of system x(c)- (xCT(-/-)) do not have a lower hippocampal glutathione content, increased oxidative stress or brain atrophy, nor exacerbated spatial reference memory deficits with aging. Together these results indicate that loss of system x(c)- does not induce oxidative stress in vivo. Young xCT(-/-) mice did however display a spatial working memory deficit. Interestingly, we observed significantly lower extracellular hippocampal glutamate concentrations in xCT(-/-) mice compared to wild-type littermates. Moreover, intrahippocampal perfusion with system x(c)- inhibitors lowered extracellular glutamate, whereas the system x(c)- activator N-acetylcysteine elevated extracellular glutamate in the rat hippocampus. This indicates that system x(c)- may be an interesting target for pathologies associated with excessive extracellular glutamate release in the hippocampus. Correspondingly, xCT deletion in mice elevated the threshold for limbic seizures and abolished the proconvulsive effects of N-acetylcysteine. These novel findings sustain that system x(c)-) is an important source of extracellular glutamate in the hippocampus. System x(c)(-) is required for optimal spatial working memory, but its inactivation is clearly beneficial to decrease susceptibility for limbic epileptic seizures.


Subject(s)
Amino Acid Transport System y+/physiology , Extracellular Space/metabolism , Glutamic Acid/metabolism , Hippocampus/physiology , Limbic System/physiology , Memory, Short-Term/physiology , Oxidative Stress/physiology , Seizures/physiopathology , Space Perception/physiology , Animals , Blotting, Western , Brain/anatomy & histology , DNA/genetics , Electroencephalography , Genotype , Glutathione/metabolism , Immunohistochemistry , Male , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Microdialysis , Motor Activity/physiology , Neuroglia/physiology , Psychomotor Performance/physiology , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Seizures/chemically induced , Seizures/genetics
9.
J Alzheimers Dis ; 24(2): 287-300, 2011.
Article in English | MEDLINE | ID: mdl-21297271

ABSTRACT

Using 8- and 18-month-old AßPP23 mice, we investigated the involvement of high-affinity glutamate transporters (GLAST, GLT-1, EAAC1), vesicular glutamate transporters (VGLUT1-3) and xCT, the specific subunit of system x(c)⁻, in Alzheimer's disease (AD) pathogenesis. Transporter expression was studied in cortical and hippocampal tissue and linked to extracellular glutamate and glutamate reuptake activity as measured using in vivo microdialysis. In 8-month-old animals, we could not observe plaque formation or gliosis. Yet, in hippocampus as well as cortex GLAST and GLT-1 expression was decreased. Whereas in cortex this was accompanied by upregulated VGLUT1 expression, extracellular glutamate concentrations were decreased. Surprisingly, inhibiting glutamate reuptake with TBOA revealed increased glutamate reuptake activity in cortex of AßPP23 mice, despite decreased GLAST and GLT-1 expression, and resulted in status epilepticus in all AßPP23 mice, contrary to wildtype littermates. In hippocampus of 8-month-old AßPP23 mice, we observed increased EAAC1 expression besides the decrease in GLAST and GLT-1. Yet, glutamate reuptake activity was drastically decreased according to the decreased GLAST and GLT-1 expression. In 18-month-old AßPP23 mice, plaque formation and gliosis in cortex and hippocampus were accompanied by decreased GLT-1 expression. We also showed, for the first time, increased cortical expression of VGLUT3 and xCT together with a strong tendency towards increased cortical extracellular glutamate levels. VGLUT2 expression remained unaltered in all conditions. The present findings support the hypothesis that alterations in transport of glutamate, and more particular via GLT-1, may be involved in AD pathogenesis.


Subject(s)
Aging , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amino Acid Transport System X-AG/metabolism , Cerebral Cortex/metabolism , Hippocampus/metabolism , Alzheimer Disease/genetics , Amino Acid Transport System X-AG/classification , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Chromatography, High Pressure Liquid , Disease Models, Animal , Excitatory Amino Acid Transporter 2/genetics , Excitatory Amino Acid Transporter 2/metabolism , Gene Expression Regulation/genetics , Glutamic Acid , Humans , Mice , Mice, Transgenic , Mutation/genetics
10.
Neurochem Int ; 55(1-3): 41-4, 2009.
Article in English | MEDLINE | ID: mdl-19171171

ABSTRACT

Glutamate, the most abundant excitatory neurotransmitter in the central nervous system, is well known to be implicated in epileptic seizures. Therefore, impairments in glutamate transport could have an involvement in the mechanism of epileptogenesis. The uptake of glutamate into synaptic vesicles is mediated by vesicular glutamate transporters (vGLUTs). There are three known vGLUT isoforms, vGLUT1-3. In this study, we are particularly interested in the vGLUT2 isoform. We investigated the possible role of vGLUT2 in pentylenetetrazol (PTZ)-induced seizure generation. Seizure threshold of PTZ was compared in vGLUT2 heterozygous knock out (HET) and wild type (WT) mice. In comparison with their WT littermates a lower dose of PTZ was needed in the vGLUT2 HET mice until the onset of the first myoclonic jerk. The threshold for PTZ-induced clonic seizure activity was also lower in the vGLUT2 HET mice. These results indicate, for the first time, that vGLUT2 is likely involved in the epileptogenesis of generalized seizures.


Subject(s)
Epilepsy, Tonic-Clonic/chemically induced , Epilepsy, Tonic-Clonic/genetics , Seizures/chemically induced , Seizures/genetics , Vesicular Glutamate Transport Protein 2/genetics , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/physiology , Convulsants , Electroencephalography , Epilepsy, Generalized/chemically induced , Epilepsy, Generalized/genetics , Heterozygote , Male , Mice , Mice, Knockout , Neural Pathways/drug effects , Neural Pathways/physiology , Pentylenetetrazole , Telemetry , Thalamus/drug effects , Thalamus/physiology
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