Glutamate Receptor Agonist Research Articles

Total synthesis of biologically active natural products based on highly selective synthetic methodologies.

Total syntheses of structurally and biologically intriguing natural products relying on new synthetic methodologies are described. This article features cinchona alkaloid-catalyzed asymmetric Morita-Baylis-Hillman reactions, heterocycle syntheses based on rhodium-catalyzed C-H amination and indium-catalyzed Conia-ene reactions, and their utilization for the syntheses of the phoslactomycin family of antibiotics, glutamate receptor agonists and antagonists, and alkaloids with characteristic highly substituted pyrrolidinone core structures.

Qualification of LSP1-2111 as a Brain Penetrant Group III Metabotropic Glutamate Receptor Orthosteric Agonist.

LSP1-2111 is a group III metabotropic glutamate receptor agonist with preference toward the mGlu4 receptor subtype. This compound has been extensively used as a tool to explore the pharmacology of mGlu4 receptor activation in preclinical animal behavioral models. However, the blood-brain barrier penetration of this amino acid derivative has never been studied. We report studies on the central nervous system (CNS) disposition of LSP1-2111 using quantitative microdialysis in rat. Significant unbound concentrations of the drug relative to its in vitro binding affinity and functional potency were established in extracellular fluid (ECF). These findings support the use of LSP1-2111 to study the CNS pharmacology of mGlu4 receptor activation through orthosteric agonist mechanisms.

Altered object exploration but not temporal order memory retrieval in an object recognition test following treatment of rats with the group II metabotropic glutamate receptor agonist LY379268

Temporal order memory refers to the ability to distinguish past experiences in the order that they occurred. Temporal order memory for objects is often tested in rodents using spontaneous object recognition paradigms. The circuitry mediating memory in these tests is distributed and involves ionotropic glutamate receptors in the perirhinal cortex and medial prefrontal cortex. It is unknown what role, if any, metabotropic glutamate receptors have in temporal order memory for objects. The present experiment examined the role of metabotropic glutamate receptors in temporal memory retrieval using the group II metabotropic glutamate receptor selective agonist LY379268. Rats were trained on a temporal memory test with three phases: two sample phases (60min between them) in which rats explored two novel objects and a test phase (60min after the second sample phase) which included a copy of each object previously encountered. Under these conditions, we confirmed that rats showed a significant exploratory preference for the object presented during the first sample phase. In a second experiment, we found that LY379268 (0.3, 1.0, or 3.0mg/kg; i.p.; 30min before the test phase) had no effect on temporal memory retrieval but dose-dependently reduced time spent exploring the objects. Our results show that enhancing mGluR2 activity under conditions when TM is intact does not influence memory retrieval.

Cytoprotection by endogenous zinc in the vertebrate retina

Our recent studies have shown that endogenous zinc, co-released with glutamate from the synaptic terminals of vertebrate retinal photoreceptors, provides a feedback mechanism that reduces calcium entry and the concomitant vesicular release of glutamate. We hypothesized that zinc feedback may serve to protect the retina from glutamate excitotoxicity, and conducted in vivo experiments on the retina of the skate (Raja erinacea) to determine the effects of removing endogenous zinc by chelation. These studies showed that removal of zinc by injecting the zinc chelator histidine results in inner retinal damage similar to that induced by the glutamate receptor agonist kainic acid. In contrast, when an equimolar quantity of zinc followed the injection of histidine, the retinal cells were unaffected. Our results are a good indication that zinc, co-released with glutamate by photoreceptors, provides an auto-feedback system that plays an important cytoprotective role in the retina.

Fluorescent imaging reports an extracellular alkalinization induced by glutamatergic activation of isolated retinal horizontal cells

Extracellular acidification induced by retinal horizontal cells has been hypothesized to underlie lateral feedback inhibition onto vertebrate photoreceptors. To test this hypothesis, the H(+)-sensitive fluorophore 5-hexadecanoylaminofluorescein (HAF) was used to measure changes in H(+) from horizontal cells isolated from the retina of the catfish. HAF staining conditions were modified to minimize intracellular accumulation of HAF and maximize membrane-associated staining, and ratiometric fluorescent imaging of cells displaying primarily membrane-associated HAF fluorescence was conducted. Challenge of such HAF-labeled cells with glutamate or the ionotropic glutamate receptor agonist kainate produced an increase in the fluorescence ratio, consistent with an alkalinization response of +0.12 pH units and +0.23 pH units, respectively. This alkalinization was blocked by the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), the L-type calcium channel blocker nifedipine, and lanthanum. The alkalinization reported by HAF was consistent with extracellular alkalinizations detected in previous studies using self-referencing H(+)-selective microelectrodes. The spatial distribution of the kainate-induced changes in extracellular H(+) was also examined. An overall global alkalinization around the cell was observed, with no obvious signs of discrete centers of acidification. Taken together, these data argue against the hypothesis that glutamatergic-induced efflux of protons from horizontal cells mediates lateral feedback inhibition in the outer retina.

Modulation of Hippocampus-Prefrontal Cortex Synaptic Transmission and Disruption of Executive Cognitive Functions by MK-801

Noncompetitive N-methyl-d-aspartate receptor antagonists such as phencyclidine and MK-801 are known to impair cognitive function in rodents and humans, and serve as a useful tool to study the cellular basis for pathogenesis of schizophrenia cognitive symptoms. In the present study, we tested in rats the effect of MK-801 on ventral hippocampus (HPC)-medial prefrontal cortex (mPFC) synaptic transmission and the performance in 2 cognitive tasks. We found that single injection of MK-801 (0.1 mg/kg) induced gradual and long-lasting increases of the HPC-mPFC response, which shares the common expression mechanisms with long-term potentiation (LTP). But unlike LTP, its induction required no enhanced or synchronized synaptic inputs, suggesting aberrant characteristics. In parallel, rats injected with MK-801 showed impairments of mPFC-dependent cognitive flexibility and HPC-mPFC pathway-dependent spatial working memory. The effects of MK-801 on HPC-mPFC responses and spatial working memory decayed in parallel within 24 h. Moreover, the therapeutically important subtype 2/3 metabotropic glutamate receptor agonist LY379268, which blocked MK-801-induced potentiation, ameliorated the MK-801-induced impairment of spatial working memory. Our results show a novel form of use-independent long-lasting potentiation in HPC-mPFC pathway induced by MK-801, which is associated with impairment of HPC-mPFC projection-dependent cognitive function.

An Acute Glutamate Exposure Induces Long-Term Down Regulation of GLAST/EAAT1 Uptake Activity in Cultured Bergmann Glia Cells

Glutamate, the major excitatory neurotransmitter in the vertebrate brain, is a potent neurotoxin therefore its extracellular levels have to be tightly regulated by means of sodium-dependent glutamate uptake systems of the slc1A family. The glial glutamate/aspartate transporter (GLAST/EAAT1) and the glutamate transporter 1 carry most of the uptake activity in cerebellum and in the forebrain, respectively. In the cerebellar cortex, GLAST is profusely expressed in Bergmann glia cells, which completely enwrap the parallel fiber-Purkinje cells synapses. Glutamate exposure in these cells, down regulates the activity as well as the expression levels of this transporter. In order to characterize the persistence of a single glutamate exposure, we followed the [(3)H]-D-aspartate uptake activity as a function of time after the removal of the glutamatergic stimulus. We were able to demonstrate that a single 30 min exposure to glutamate reduces the uptake activity for up to 3 h. This effect is dose-dependent and it is not reproduced neither by ionotropic nor metabotropic glutamate receptors agonists. In contrast, transporter specific ligands such as D-aspartate or L-(-)-threo-3-Hydroxyaspartic acid fully reproduce the glutamate effect. Equilibrium binding experiments revealed a decrease in [(3)H]-D-aspartate Bmax without a significant change in affinity, clearly suggesting that a reduction in the availability of plasma membrane glutamate transporters is the molecular basis of this effect. Interestingly, neither Glast mRNA nor its protein levels were significantly reduced upon the single glutamate exposure. Taken together, these results favor the notion of a transporter-mediated tight control of the uptake process.

Effects of Blockade of Dopamine D2 Receptors on the Activity of the Nitrergic System of the Nucleus Accumbens in the Rat Brain

In vivo intracerebral microdialysis studies with high-performance liquid chromatography and electrochemical detection in Sprague–Dawley rats showed that administration of the dopamine D2 receptor antagonist raclopride (20 and 100 μM) into the nucleus accumbens did not alter the baseline extracellular citrulline level (a co-product of NO synthesis) in the nucleus accumbens. Administration of NMDA (100 μM), an NMDA glutamate receptor agonist, into the nucleus accumbens induced an increase in the extracellular citrulline level in this structure. Administration of 7-nitroindazole (0.5 mM), an inhibitor of the neuronal isoform of NO synthase, into the nucleus accumbens blocked this increase, while administration of raclopride (20 and 100 μM) into this structure decreased the increase. These data suggest that dopamine D2 receptors in the nucleus accumbens are involved in regulation of the extent of activation of neuronal NO synthase induced by local stimulation of NMDA glutamate receptors.

Involvement of NMDA receptor in low-frequency magnetic field-induced anxiety in mice

It had been reported that exposure to extremely low-frequency magnetic field (ELFMF) induces anxiety in human and rodents. Anxiety mediates via the activation of N-methyl-d-aspartate (NMDA) receptor, whereas activation of γ-aminobutyric acid (GABA) receptor attenuates the same. Hence, the present study was carried out to understand the contribution of NMDA and/or GABA receptors modulation in ELFMF-induced anxiety for which Swiss albino mice were exposed to ELFMF (50 Hz, 10 G) by subjecting them to Helmholtz coils. The exposure was for 8 h/day for 7, 30, 60, 90 and 120 days. Anxiety level was assessed in elevated plus maze, open field test and social interaction test, on 7th, 30th, 60th, 90th and 120th exposure day, respectively. Moreover, the role of GABA and glutamate in ELFMF-induced anxiety was assessed by treating mice with muscimol [0.25 mg/kg intraperitoneally (i.p.)], bicuculline (1.0 mg/kg i.p.), NMDA (15 mg/kg i.p.) and MK-801 (0.03 mg/kg i.p.), as a GABAA and NMDA receptor agonist and antagonist, respectively. Glutamate receptor agonist exacerbated while inhibitor attenuated the ELFMF-induced anxiety. In addition, levels of GABA and glutamate were determined in regions of the brain viz, cortex, striatum, hippocampus and hypothalamus. Experiments demonstrated significant elevation of GABA and glutamate levels in the hippocampus and hypothalamus. However, GABA receptor modulators did not produce significant effect on ELFMF-induced anxiety and elevated levels of GABA at tested dose. Together, these findings suggest that ELFMF significantly induced anxiety behavior, and indicated the involvement of NMDA receptor in its effect.

P.1.g.067 Tianeptine has neuroprotective effects in a differentiated SH-SY5Y human neuroblastoma cell line

The inferior colliculus (IC) is an important midbrain relay station for the integration of descending and ascending auditory information. In addition, it has also been implicated in the processing of acoustic information of aversive nature, as well as in sensory-motor gating. There is evidence that glutamate-mediated mechanisms at the IC level influence haloperidol-induced catalepsy. The present study investigated the influence of glutamate-mediated mechanisms in the IC on catalepsy induced by intrastriatal microinjection of haloperidol (10 μg/0.5 μl). Male Wistar rats received bilateral intracollicular microinjections of the glutamate receptor agonist NMDA (10 or 20 nmol/0.5 μl), the NMDA receptor antagonists MK-801 (15 or 30 nmol/0.5 μl) or physiological saline (0.5 μl), followed by bilateral microinjections of haloperidol (10 μg/0.5 μl) or vehicle (0.5 μl) into the dorso-rostral or ventro-rostral striatum. The catalepsy test was performed positioning both forepaws of the rats on an elevated horizontal wooden bar and recording the time during which the animal remained in this position. The results showed that the administration of physiological saline in the IC followed by the microinjection of haloperidol in the dorso-rostral region of the striatum was not able to induce catalepsy. However, when the bilateral administration of NMDA into the IC was followed by microinjection of haloperidol into the dorso-rostral striatum, catalepsy was observed. The microinjection of haloperidol into the ventro-rostral striatum induced catalepsy, counteracted by previous administration of MK-801 into the IC. These findings suggest that glutamate-mediated mechanisms in the IC can influence the intrastriatal haloperidol-induced catalepsy and that the IC plays an important role as a sensorimotor interface.

Glutamate Receptors and Presympathetic Neuronal Hyperactivity of the Central Nervous System in Hypertension

We read with great interest the article by Dr Ye et al1 dealing with the relationships between group II metabotropic glutamate receptors and activities of presympathetic neurons in hypothalamic periventricular nucleus (PVN) in hypertension. The results of their study demonstrated that by using the brain slice preparation, group II metabotropic glutamate receptors agonist (2S, 2′R, 3′R)-2-(2′, 3′-dicarboxycyclopropyl)glycine (DCG-IV) produced a greater reduction in the frequency of spontaneous and miniature excitatory postsynaptic currents and in the amplitude of electrically evoked excitatory postsynaptic currents in retrogradely labeled spinally …

Group I metabotropic glutamate receptors in the medial prefrontal cortex: Role in mesocorticolimbic glutamate release in cocaine sensitization

Cocaine sensitization is associated with increased excitability of pyramidal projection neurons in the medial prefrontal cortex. Such hyperexcitability is presumed to increase glutamatergic input to the nucleus accumbens and ventral tegmental area. This study examined the effects of medial prefrontal cortex Group I metabotropic glutamate receptor activation on glutamate levels in the medial prefrontal cortex, nucleus accumbens, and ventral tegmental area in sensitized and control animals. Male Sprague-Dawley rats received four daily injections of cocaine (15 mg/kg, i.p.) or saline (1 mL/kg i.p.). One, 7, or 21 days from the fourth injection, dual-probe microdialysis experiments were performed wherein Group I metabotropic glutamate receptor agonist DHPG was infused into the medial prefrontal cortex and glutamate levels in this region as well as the nucleus accumbens or ventral tegmental area were examined. Intra-mPFC DHPG infusion increased glutamate levels in the medial prefrontal cortex at 1 and 7 days withdrawal, and in the nucleus accumbens at 21 days withdrawal in sensitized rats. These results suggest Group I metabotropic glutamate receptor activation may contribute to the increased excitability of medial prefrontal cortex pyramidal neurons in sensitized animals.

Phospholipase D-mediated hypersensitivity at central synapses is associated with abnormal behaviours and pain sensitivity in rats exposed to prenatal stress

Adverse events at critical stages of development can lead to lasting dysfunction in the central nervous system (CNS). To seek potential underlying changes in synaptic function, we used a newly developed protocol to measure alterations in receptor-mediated Ca2+ fluorescence responses of synaptoneurosomes, freshly isolated from selected regions of the CNS concerned with emotionality and pain processing. We compared adult male controls and offspring of rats exposed to social stress in late pregnancy (prenatal stress, PS), which showed programmed behavioural changes indicating anxiety, anhedonia and pain hypersensitivity. We found corresponding increases, in PS rats compared with normal controls, in responsiveness of synaptoneurosomes from frontal cortex to a glutamate receptor (GluR) agonist, and from spinal cord to activators of nociceptive afferents. Through a combined pharmacological and biochemical strategy, we found evidence for a role of phospholipase D1 (PLD1)-mediated signalling, that may involve 5-HT2A receptor (5-HT2AR) activation, at both levels of the nervous system. These changes might participate in underpinning the enduring alterations in behaviour induced by PS.

The group II metabotropic glutamate receptor agonist, LY379268, decreases methamphetamine self-administration in rats

BackgroundGiven the problems associated with the escalation in methamphetamine (METH) use, the identification of more effective treatment strategies is essential. Group II metabotropic glutamate receptors (mGluRs) have been suggested to be a novel therapeutic target for psychostimulant addiction. We sought to test the ability of the selective group II mGluR agonist LY379268 to reduce METH self-administration in rats. MethodsRats were trained to self-administer METH on a progressive ratio (PR) schedule. Animals were then switched to fixed ratio responding and given daily extended access (6h/day) to METH self-administration for 14 days. Rats were then re-tested on the PR schedule. The effect of LY379268 on METH-reinforced PR responding was determined before and after 14 days of extended access. To test for non-specific effects, a separate group of animals received LY379268 prior to a sucrose pellet-reinforced PR schedule. ResultsAnimals escalated their daily intake of METH during extended access. PR responding did not change as a function of extended access. LY379268 significantly attenuated METH reinforced responding, both before and after extended access. The degree of attenuation did not change as a function of extended access. LY379268 had no effect on sucrose pellet-reinforced responding at any dose. ConclusionsLY379268 selectively reduced the motivation to self-administer METH. In contrast to data with other compounds, the sensitivity to the effects of LY379268 did not change following extended access to METH self-administration. Group II mGluR agonists, therefore, may represent a relatively new class of compounds for the development of pharmacotherapies for METH addiction.

Evidence for Glutamate as a Neuroglial Transmitter within Sensory Ganglia

This study examines key elements of glutamatergic transmission within sensory ganglia of the rat. We show that the soma of primary sensory neurons release glutamate when depolarized. Using acute dissociated mixed neuronal/glia cultures of dorsal root ganglia (DRG) or trigeminal ganglia and a colorimetric assay, we show that when glutamate uptake by satellite glial cells (SGCs) is inhibited, KCl stimulation leads to simultaneous increase of glutamate in the culture medium. With calcium imaging we see that the soma of primary sensory neurons and SGCs respond to AMPA, NMDA, kainate and mGluR agonists, and selective antagonists block this response. Using whole cell patch-clamp technique, inward currents were recorded from small diameter (<30 µm) DRG neurons from intact DRGs (ex-vivo whole ganglion preparation) in response to local application of the above glutamate receptor agonists. Following a chronic constriction injury (CCI) of either the inferior orbital nerve or the sciatic nerve, glutamate expression increases in the trigeminal ganglia and DRG respectively. This increase occurs in neurons of all diameters and is present in the somata of neurons with injured axons as well as in somata of neighboring uninjured neurons. These data provides additional evidence that glutamate can be released within the sensory ganglion, and that the somata of primary sensory neurons as well as SGCs express functional glutamate receptors at their surface. These findings, together with our previous gene knockdown data, suggest that glutamatergic transmission within the ganglion could impact nociceptive threshold.

Application of imaging technique for characterization of ionotropic glutamate receptor ligands in cultured neurons

This article presents a non-invasive microphotometrical method for identification and the quantitative analysis of the compounds interacting with glutamate NMDA, AMPA, and KA-receptors. The method is based on the registration of ligand-gated and voltage-gated calcium channels activity using ratiometric fluorescent probe Fura-2. We have found conditions when repeated short-term (up to 30 s) applications of NMDA-, AMPA- and kainate-receptor agonists induce in most cells a calcium response almost identical to the first one. In the experiment we used the cell reaction to the first ligand application as a control, which significantly simplified the process of ligand titration. The optimal culture age was determined to enhance sensitivity of the method for each ligand. Certain rules of signal normalization were established to compare the results of different experiments and to obtain more precise values of activation and inhibition constants. It has been shown that the variability of calcium responses of individual neurons to the glutamate receptor agonists significantly depends on the degree and kinetics of their desensitization. The AMPA and KA-receptor ligands were characterized in the experiments performed in the presence of desensitization inhibitors cyclothiazide and concanavalin A, respectively. The inhibitors increased the amplitude of the response and converted the transient responses into the step ones. The method permits the detection of receptor ligands under study in an unknown sample, as well as determination of the activation and inhibition constants and the type of the inhibition. The method combines, high sensitivity, specificity and performance due to the possibility of analyzing individual activities of hundreds of cells simultaneously. The method can be used to obtain both the averaged response for all of the studied neurons and the responses of the selected cell populations or single neurons.

Neuronal transporter and astrocytic ATP exocytosis underlie activity‐dependent adenosine release in the hippocampus

The neuromodulator adenosine plays an important role in many physiological and pathological processes within the mammalian CNS. However, the precise mechanisms of how the concentration of extracellular adenosine increases following neural activity remain contentious. Here we have used microelectrode biosensors to directly measure adenosine release induced by focal stimulation in stratum radiatum of area CA1 in mouse hippocampal slices. Adenosine release was both action potential and Ca²⁺ dependent and could be evoked with low stimulation frequencies and small numbers of stimuli. Adenosine release required the activation of ionotropic glutamate receptors and could be evoked by local application of glutamate receptor agonists. Approximately 40% of stimulated-adenosine release occurred by translocation of adenosine via equilibrative nucleoside transporters (ENTs). This component of release persisted in the presence of the gliotoxin fluoroacetate and thus results from the direct release of adenosine from neurons. A reduction of adenosine release in the presence of NTPDase blockers, in slices from CD73(-/-) and dn-SNARE mice, provides evidence that a component of adenosine release arises from the extracellular metabolism of ATP released from astrocytes. This component of release appeared to have slower kinetics than the direct ENT-mediated release of adenosine. These data suggest that activity-dependent adenosine release is surprisingly complex and, in the hippocampus, arises from at least two distinct mechanisms with different cellular sources.

Regulation of Hypothalamic Presympathetic Neurons and Sympathetic Outflow by Group II Metabotropic Glutamate Receptors in Spontaneously Hypertensive Rats

Increased glutamatergic input in the hypothalamic paraventricular nucleus (PVN) plays an important role in the development of hypertension. Group II metabotropic glutamate receptors are expressed in the PVN, but their involvement in regulating synaptic transmission and sympathetic outflow in hypertension is unclear. Here, we show that the group II metabotropic glutamate receptors agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) produced a significantly greater reduction in the frequency of spontaneous and miniature excitatory postsynaptic currents and in the amplitude of electrically evoked excitatory postsynaptic currents in retrogradely labeled spinally projecting PVN neurons in spontaneously hypertensive rats (SHRs) than in normotensive control rats. DCG-IV similarly decreased the frequency of GABAergic inhibitory postsynaptic currents of labeled PVN neurons in the 2 groups of rats. Strikingly, DCG-IV suppressed the firing of labeled PVN neurons only in SHRs. DCG-IV failed to inhibit the firing of PVN neurons of SHRs in the presence of ionotropic glutamate receptor antagonists. Lowering blood pressure with celiac ganglionectomy in SHRs normalized the DCG-IV effect on excitatory postsynaptic currents to the same level seen in control rats. Furthermore, microinjection of DCG-IV into the PVN significantly reduced blood pressure and sympathetic nerve activity in SHRs. Our findings provide new information that presynaptic group II metabotropic glutamate receptor activity at the glutamatergic terminals increases in the PVN in SHRs. Activation of group II metabotropic glutamate receptors in the PVN inhibits sympathetic vasomotor tone through attenuation of increased glutamatergic input and neuronal hyperactivity in SHRs.

Group II Metabotropic Glutamate Receptor Agonist LY379268 Regulates AMPA Receptor Trafficking in Prefrontal Cortical Neurons

Group II metabotropic glutamate receptor (mGluR) agonists have emerged as potential treatment drugs for schizophrenia and other neurological disorders, whereas the mechanisms involved remain elusive. Here we examined the effects of LY379268 (LY37) on the expression and trafficking of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits GluA1 and GluA2 in prefrontal neurons. We show that LY37 significantly increased the surface and total expression of both GluA1 and GluA2 subunits in cultured prefrontal neurons and in vivo. This effect was mimicked by the selective mGluR2 agonist LY395756 and was blocked by mGluR2/3 antagonist LY341495. Moreover, we found that both GluA1 and GluA2 subunits were colocalized with PSD95 but not synapsin I, suggesting a postsynaptic localization. Consistently, treatment with LY37 significantly increased the amplitude, but not frequency, of miniature excitatory postsynaptic currents. Further, actinomycin-D blocked LY37's effects, suggesting a transcriptional regulation. In addition, application of glycogen synthase kinase-3beta (GSK-3β) inhibitor completely blocked LY37's effect on GluA2 surface expression, whereas GSK-3β inhibitor itself induced decreases in the surface and total protein levels of GluA1, but not GluA2 subunits. This suggests that GSK-3β differentially mediates GluA1 and GluA2 trafficking. Further, LY37 significantly increased the phosphorylation, but not total protein, of extracellular signal-regulated kinase 1/2 (ERK1/2). Neither ERK1/2 inhibitor PD98059 alone nor PD98059 combined with LY37 treatment induced changes in GluA1 or GluA2 surface expression or total protein levels. Our data thus suggest that mGluR2/3 agonist regulates postsynaptic AMPA receptors by affecting the synaptic trafficking of both GluA1 and GluA2 subunits and that the regulation is likely through ERK1/2 signaling in GluA1 and/or both ERK1/2 and GSK-3β signaling pathways in the GluA2 subunit.

Striatal Glutamate Degenerates Thalamic Neurons

Glutamate (GLU)-induced excitotoxicity is considered to be a frequent cause of cell degeneration in basal ganglia disorders; it is normally prevented by uptake of GLU by astrocytes. We recently found that transient perfusion of GLU in the striatum induces persistent accumulation of GLU in striatal astrocytes that could be from the initial administration or caused by the slow release from neurons or astrocytes in response to it. Endogenous production of GLU, that is, "self-induced GLU accumulation" (SIGA), may occur under physiological and pathological conditions. Here we studied the possible induction of SIGA after injury induced by perfusion of GLU receptor agonists into the striatum of rats. The agonists induced local degeneration in neurons and myelinated axons and microgliosis and astrocytosis; there was also gliosis and remote degeneration of neurons in the ventral-posterior complex of the thalamus that project to the cerebral cortex across the striatum. Reactive astrocytes showed persistent GLU accumulation in the striatum (local SIGA) and thalamus (remote SIGA) that persisted for at least 6 weeks after the injury. Thus, SIGA can be induced by neuronal degeneration retrogradely triggered from a remote brain region after excessive release of endogenous GLU from astrocytes. This may be an additional factor to be considered in basal ganglia disorders with glutamatergic excitotoxicity.