Metabotropic glutamate receptors prevent nitric oxide-induced programmed cell death

Activation of metabotropic glutamate receptor (mGluR) subtypes can prevent neuronal injury through the signal transduction pathways of nitric oxide (NO). It is this link to NO free radical injury and subsequent DNA damage that is the most intriguing. We therefore examined whether neuronal protection through mGluR activation was dependent on the molecular mechanisms of programmed cell death (PCD). The NO generators sodium nitroprusside and 3-morpholino-sydnonimine were administered to induce NO toxicity in primary hippocampal neurons. PCD was documented by hematoxylin and eosin nuclear staining, DNA gel electrophoresis, transmission electron microscopy, and protein synthesis assays. Following NO exposure, PCD induction was rapid and robust in approximately 70% of the neuronal population. Activation of specific mGluR subtypes with 1S,3R-ACPD and L-AP4, agents that are neuroprotective against NO, significantly limited the progression of PCD. In contrast, antagonism of mGluRs with L-AP3 did not prevent the development of PCD. Induction of new protein synthesis, a common requisite for PCD, was evident following NO exposure, but did not appear to represent a principal pathway of modulation by the mGluR agonists. Our studies suggest that mGluR modulation of NO-induced PCD represents a primary molecular pathway responsible for neuronal survival. Further elucidation of the molecular mGluR signaling pathways may yield new insight into specific genetic regulatory mechanisms responsible for neuronal injury. J. Neurosci. Res. 50: 549–564, 1997. © 1997 Wiley-Liss, Inc.     

Driving cellular plasticity and survival through the signal transduction pathways of metabotropic glutamate receptors

Metabotropic glutamate receptors (mGluRs) share a common molecular morphology with other G protein-linked receptors, but there expression throughout the mammalian nervous system places these receptors as essential mediators not only for the initial development of an organism, but also for the vital determination of a cell's fate during many disorders in the nervous system that include amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, Multiple Sclerosis, epilepsy, trauma, and stroke. Given the ubiquitous distribution of these receptors, the mGluR system impacts upon neuronal, vascular, and glial cell function and is activated by a wide variety of stimuli that includes neurotransmitters, peptides, hormones, growth factors, ions, lipids, and light. Employing signal transduction pathways that can modulate both excitatory and inhibitory responses, the mGluR system drives a spectrum of cellular pathways that involve protein kinases, endonucleases, cellular acidity, energy metabolism, mitochondrial membrane potential, caspases, and specific mitogen-activated protein kinases. Ultimately these pathways can converge to regulate genomic DNA degradation, membrane phosphatidylserine (PS) residue exposure, and inflammatory microglial activation. As we continue to push the envelope for our understanding of this complex and critical family of metabotropic receptors, we should be able to reap enormous benefits for both clinical disease as well as our understanding of basic biology in the nervous system.     

Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer’s disease

Selective neuronal dysfunction and degeneration are defining features of Alzheimers disease (AD). While the exact mechanism(s) contributing to this selective neuronal vulnerability remains to be elucidated, we hypothesized that the differential expression of metabotropic glutamate receptors (mGluRs) may play a key role in this process since the various mGluR groups differentially regulate neuronal cell death and survival. In the present study, we focused on the metabotropic glutamate receptor 2 (mGluR2), a subtype of group II mGluRs. The mGluR2 is expressed at low levels in pyramidal neurons in age-matched control cases, whereas we found a strikingly increased mGluR2 expression in AD, in a pattern that mirrored both the regional and cellular subtype of neuronal vulnerability to degeneration and neurofibrillary alterations. Immunoblot analysis confirmed the significant increase in the level of mGluR2 in AD compared with age-matched controls. Agonists for group II mGluRs activate extracellular receptor kinase (ERK), a kinase that is chronically activated in vulnerable neurons of AD. ERK is able to phosphorylate tau protein, so the up-regulation of mGluR2 in vulnerable neurons may represent the upstream mediator of abnormal tau phosphorylation in AD. Immunocytochemical examination revealed considerable overlap between mGluR2 and neurofibrillary alterations. Thus, it is likely that mGluR2 represents a novel therapeutic target for AD.     

Differential effects of the group II mGluR agonist, DCG-IV, on depolarization-induced suppression of inhibition in hippocampal CA1 and CA3 neurons

We investigated the role of metabotropic glutamate receptors in the mediation of depolarization-induced suppression of inhibition (DSI), using whole-cell electrophysiological techniques in rat hippocampal slice preparation. In a previous work, we showed that a retrograde signal travels from CA1 pyramidal cells to GABA interneurons and prevents them from releasing GABA for tens of seconds at 30 degrees C. The resulting suppression of inhibition is DSI. The retrograde signal appeared to be glutamate, or a glutamate analog, which acted on group I metabotropic receptors on the interneurons. It is not known if DSI occurs in hippocampal subregions besides CA1. If DSI does occur in other regions, it will be important to know if the role of metabotropic glutamate receptors (mGluRs) in mediating DSI is the same everywhere. The distribution of mGluR subtypes varies among hippocampal subregions. In the CA3 region, unlike CA1, group II mGluRs are prevalent. It was possible, therefore, that in CA3, the group II mGluRs would mediate DSI. We have begun to investigate these issues. We now report that: 1) DSI does occur in CA3. 2) Carbachol induces IPSC activity that can be recorded in CA1 and CA3a. This carbachol-induced activity can be reduced by the selective group II mGluR agonist, DCG-IV, and by DSI. 3) Evoked IPSCs in CA3a, but not in CA1, can be reduced by DCG-IV; hence the interneurons activated by carbachol may reside in CA3a. 4) Despite the group II mGluR agonist sensitivity of CA3a interneurons, DSI in this region is not affected by a group II mGluR antagonist, CPPG, and therefore does not appear to be mediated by group II mGluRs.     

The metabotropic glutamate system promotes neuronal survival through distinct pathways of programmed cell death

Activation of the metabotropic glutamate receptor (mGluR) system can prevent free radical, nitric oxide (NO)-induced programmed cell death (PCD). To investigate the mechanisms utilized by the mGluR system to regulate the induction of PCD, we examined the course of PCD in real time in individual, living, primary hippocampal neurons. We assessed both phosphatidylserine (PS) externalization, an early event in PCD, and DNA fragmentation during NO toxicity and mGluR modulation to determine the individual contributions of PS externalization and genomic DNA fragmentation during neuronal PCD. Exposure to the NO donors (300 microM SNP or 300 microM NOC-9) induced PCD in approximately 75% of neurons over a 24-h period. The externalization of PS in neurons increased to 21 +/- 2% as early as 3 h following NO exposure and then increased to 80 +/- 2% over a 24-h period. The externalization of PS was independent of the loss of membrane integrity. Agonists for individual mGluR subgroups were equally able to prevent NO-induced neuronal death and DNA degradation, yet they possessed differential abilities to regulate PS externalization. The group I agonist DHPG (750 microM) and the group III agonist L-AP4 (750 microM) both prevented and reversed NO-induced PS externalization. In contrast, activation of group II subtypes using L-CCG-I (750 microM) did not prevent PS externalization. Employing an experimental model that independently led to the externalization of PS residues, we demonstrated that PS externalization does not immediately impact on neuronal survival. Yet, subsequent neuronal survival may ultimately depend upon preventing PS externalization to avoid neuronal tagging for phagocytosis. Since group I and III mGluR subtypes possess the unique ability to maintain genomic integrity and membrane PS asymmetry, these agents may provide superior overall protection against NO-induced neuronal injury.     

Changes in metabotropic glutamate receptor expression following spinal cord injury

Spinal cord injury (SCI) initiates biochemical events that lead to an increase in extracellular excitatory amino acid concentrations, resulting in glutamate receptor-mediated excitotoxic events. These receptors include the three groups of metabotropic glutamate receptors (mGluRs). Group I mGluR activation can initiate a number of intracellular pathways that increase neuronal excitability. Group II and III mGluRs may function as autoreceptors to modulate neurotransmission. Thus, all three groups may contribute to the mechanisms of central sensitization and chronic central pain. To begin evaluating mGluRs in SCI, we quantified the changes in mGluR expression after SCI in control (naive), sham, and impact injured adult male Sprague-Dawley rats (200-250 g). SCI was produced at spinal segment T10 with a New York University impactor (12.5-mm drop, 10-g rod of 2-mm diameter). Expression levels were determined by Western blot and immunohistochemistry analyses at the epicenter of injury, as well as segments rostral and caudal. The group I subtype mGluR1 was increased over control levels in segments rostral and caudal by postsurgical day (PSD) 7 and remained elevated through PSD 60. The group I subtype mGluR5 was unchanged in all segments rostral and caudal to the injury at every time point measured. Group II mGluRs were decreased compared to control levels from PSD 7 through PSD 60 in all segments. These results suggest that different subtypes of mGluRs have different spatial and temporal expression patterns following SCI. The expression changes in mGluRs parallel the development of mechanical allodynia and thermal hyperalgesia following SCI; therefore, understanding the expression of mGluRs after SCI may give insight into mechanisms underlying the development of chronic central pain.     

Glutamate inhibits thalamic reticular neurons.

Activation of metabotropic glutamate receptors (mGluRs) can result in long-lasting modulation of neuronal excitability. Multiple mGluR subtypes are localized within the rat thalamic reticular nucleus (TRN), and we have examined the effects of activating these different receptor subtypes on the excitability of these neurons using an in vitro slice preparation. Typical of most mGluR-sensitive preparations, the general mGluR agonist, (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD) produced a robust, long-lasting excitatory response. Surprisingly, ACPD produced a membrane hyperpolarization in some neurons. Using selective mGluR agonists, we found that activation of group II mGluRs produces the hyperpolarization, whereas the depolarization is mediated by group I mGluRs. While the polarity of the postsynaptic response (hyperpolarization vs depolarization) was dependent on the mGluR subtype activated, both actions appear to result from modification of a linear K(+) conductance. The inhibitory action of Glutamate, via group II mGluRs, provides an avenue for a disinhibitory effect that could have interesting consequences upon a well-investigated, model neuronal circuit, turning its assumed functional role upside down.     

Exacerbation of neuronal cell death by activation of group I metabotropic glutamate receptors: role of NMDA receptors and arachidonic acid release

Both ionotropic and metabotropic glutamate receptors have been implicated in the pathogenesis of neuronal injury. Activation of group I metabotropic glutamate receptors (mGluR) exacerbates neuronal cell death, whereas inhibition is neuroprotective. However, the mechanisms involved remain unknown. Activation of group I mGluR modulates multiple signal transduction pathways including stimulation of phosphoinositide hydrolysis, potentiation of NMDA receptor activity, and release of arachidonic acid. Here we demonstrate that whereas activation of group I mGluR by (S)-3,5-dihydroxyphenylglycine (DHPG) potentiates NMDA-induced currents and intracellular calcium increases in rat cortical neuronal cultures, partial effects of group I mGluR activation or inhibition on neuronal injury induced by oxygen-glucose deprivation remain despite NMDA receptor blockade. DHPG stimulation also increases basal arachidonic acid release from rat neuronal-glial cultures and potentiates injury-induced arachidonic acid release in these cultures. Thus, activation of group I mGluR may exacerbate neuronal injury through multiple mechanisms, which include positive modulation of NMDA receptors and enhanced release of arachidonic acid.     

Membrane-Localised Oestrogen Receptor α and β Influence Neuronal Activity Through Activation of Metabotropic Glutamate Receptors

Until recently, the idea that oestradiol could affect cellular processes independent of nuclear oestrogen receptors (ERs) was controversial. This was despite the large number of carefully controlled studies performed both within and outside the nervous system demonstrating that oestrogens regulate various intracellular signalling pathways by acting at the membrane surface of cells and/or at biological rates incompatible with the time course of genomic-initiated events. At present, it is far less controversial that oestradiol acts at surface membrane receptors to regulate nervous system function. Recent studies have demonstrated that the classical intracellular ERs, ERα and ERβ, are major players in mediating the actions of oestradiol on the membrane surface. This review focuses on one potential mechanism by which surface-localised ERα and ERβ stimulate intracellular signalling events in cells of the nervous system. After oestradiol treatment, both ERα and ERβ are capable of activating different classes of metabotropic glutamate receptors (mGluRs). Oestradiol activation of mGluRs is independent of glutamate, but requires expression of several different caveolin proteins to compartmentalise the different ERs with mGluRs into functional signalling microdomains. ER/mGluR signalling is a potential means by which oestrogens can both rapidly and for extended periods, influence a variety of intracellular signalling processes and behaviours.     

The role of group I metabotropic glutamate receptors in neuronal excitotoxicity in alzheimer’s disease

Neurodegenerative diseases such as Huntington's disease, ischemia, and Alzheimer's disease (AD) are major causes of death. Recently, metabotropic glutamate receptors (mGluRs), a group of seven-transmembrane-domain proteins that couple to G-proteins, have become of interest for studies of pathogenesis. Group I mGluRs control the levels of second messengers such as inositol 1,4,5-triphosphate (IP3), Ca2+ ions and cAMP. They elicit the release of arachidonic acid via intracellular Ca2+ mobilization from intracellular stores such as mitochondria and endoplasmic reticulum. This facilitates the release of glutamate and could trigger the formation of neurofibrillary tangles, a pathological hallmark of AD. mGluRs regulate neuronal injury and survival, possibly through a series of downstream protein kinase and cysteine protease signaling pathways that affect mitochondrially mediated programmed cell death. They may also play a role in glutamate-induced neuronal death by facilitating Ca(II) mobilization. Hence, mGluRs have become a target for neuroprotective drug development. They represent a pharmacological path to a relatively subtle amelioration of neurotoxicity because they serve a modulatory rather than a direct role in excitatory glutamatergic transmission.     

The role of group I and group II metabotropic glutamate receptors in modulation of striatal NMDA and quinolinic acid toxicity

Excitotoxic lesions of the striatum are mediated by the combined activity of N-methyl-d-aspartate (NMDA) receptors and metabotropic glutamate receptors (mGluRs). Intrastriatal injection of the NMDA receptor agonists NMDA or quinolinic acid creates large lesions, but in rats that have been decorticated to remove endogenous glutamatergic input, NMDA and quinolinic acid are no longer toxic. We report that NMDA toxicity can be restored in decorticated animals by coinjection of the group I mGluR agonists t-ACPD, t-ADA, or CHPG. In addition, injections of two group I mGluR antagonists, AIDA and (S)-4C3HPG, can protect against striatal lesions produced by quinolinic acid or NMDA injections in normal rats by blocking activation of group I mGluRs. The group II mGluR agonist APDC fails to protect against quinolinic acid or NMDA toxicity in intact animals or to restore NMDA toxicity in decorticated animals, suggesting that the role of group II receptors in this excitotoxic model is minimal. These observations confirm the important role of group I mGluRs in excitotoxicity and identify these receptors as promising targets for therapeutic intervention in neurodegenerative disease processes.     

Cajal-Retzius cells in early postnatal mouse cortex selectively express functional metabotropic glutamate receptors

Glutamate receptors have been linked to the regulation of several developmental events in the CNS. By using cortical slices of early postnatal mice, we show that in layer I cells, glutamate produces intracellular calcium ([Ca(2+)](i)) elevations mediated by ionotropic and metabotropic glutamate receptors (mGluRs). The contribution of mGluRs to these responses was demonstrated by application of tACPD, an agonist to groups I and II mGluRs, which evoked [Ca(2+)](i) increases that could be reversibly blocked by MCPG, an antagonist to groups I and II mGluRs. In the absence of extracellular Ca(2+), repetitive applications of tACPD or quisqualate, an agonist to group I mGluRs, elicited decreasing [Ca(2+)](i) responses that were restored by refilling a thapsigargin-sensitive Ca(2+) store. The use of specific group I mGluR agonists CHPG and DHPG indicated that the functional mGluR in layer I was of the mGluR1 subtype. Subtype specific antibodies confirmed the presence of mGlur1 alpha, but not mGluR5, in Cajal-Retzius (Reelin-immunoreactive) neurons.     

Activity-dependent induction and maintenance of epileptiform activity produced by group I metabotropic glutamate receptors in the rat hippocampal slice

Activation of group I metabotropic glutamate receptors (mGluRs) produces a long-lasting change in hippocampal excitability that persists in the absence of an agonist. Exposure to the group I mGluR agonist dihydroxyphenylglycine (DHPG) results in the induction of spontaneously occurring epileptiform activity in the CA3 region of rat hippocampal slices that includes both brief interictal discharges and longer synchronous activity that resembles seizure or ictal activity (>2s duration oscillating at a frequency greater than 2Hz). We evaluated activity-dependent mechanisms for the induction and maintenance of epileptiform activity. Both the induction and maintenance of epileptiform activity was blocked by inhibiting action potential generation with tetrodotoxin or substitution of sodium with choline or by blocking AMPA/KA ionotropic glutamate receptors. The ictal epileptiform activity induced by DHPG was composed of synchronous synaptic activity. Antagonists of group I mGluRs, either mGluR1 or mGluR5, suppressed the induction of ictal activity but had minimal effects on the maintenance of epileptiform activity. Group I mGluRs activate phospholipase C and inhibition of phospholipase C suppressed the induction but not the maintenance of epileptiform activity. Taken together, these results point to a use dependent change in CA3 neuronal network function produced by group I mGluR activation. Furthermore, activation of both mGluR1 and 5 is required to induce ictal discharges. The induction of epileptiform activity by DHPG is an in vitro model of epileptogenesis, and the development of epileptiform activity in this model depends on neuronal activity and synaptic transmission.     

Role of group II and group III metabotropic glutamate receptors in spinal cord injury.

Spinal cord injury (SCI) produces an increase in extracellular excitatory amino acid (EAA) concentrations that results in glutamate receptor-mediated excitotoxic events. An important class of these receptors is the metabotropic glutamate receptors (mGluRs). mGluRs can activate a number of intracellular pathways that increase neuronal excitability and modulate neurotransmission. Group I mGluRs are known to modulate EAA release and the development of chronic central pain (CCP) following SCI; however, the role of group II and III mGluRs remains unclear. To begin evaluating group II and III mGluRs in SCI, we administered the specific agonists for group II, APDC, or group III, L-AP4, by interspinal injection immediately following SCI. Contusion injury was produced at spinal segment T10 with a New York University impactor (12.5-mm drop, 10-g rod 2 mm in diameter) in 30 adult male Sprague-Dawley rats (175-200 g). Evoked and spontaneous behavioral measures of CCP, locomotor recovery, changes in mGluR expression, and amount of spared tissue were examined. Neither APDC nor L-AP4 affected locomotor recovery or the development of thermal hyperalgesia; however, L-AP4 and APDC attenuated changes in mechanical thresholds and changes in exploratory behavior indicative of CCP. APDC- and L-AP4-treated groups had higher expression levels of mGluR2/3 at the epicenter of injury on post contusion day 28; however, there was no difference in the amount of spared tissue between treatment groups. These results demonstrate that treatment with agonists to group II and III mGluRs following SCI affects mechanical responses, exploratory behavior, and mGluR2/3 expression without affecting the amount of tissue spared, suggesting that the level of mGluR expression after SCI may modulate nociceptive responses.     

Colocalization of metabotropic glutamate receptors in rat dorsal root ganglion cells

Glutamate is the main excitatory transmitter in both central and peripheral nervous systems. Discovery of metabotropic glutamate receptors (mGluRs) made it clear that glutamate can have excitatory or inhibitory effects on neuronal function, with group I mGluRs enhancing cell excitability but group II and III mGluRs decreasing excitability. The present study investigated the colocalization of mGluR subtypes representing groups I, II, or III in rat L5 dorsal root ganglion (DRG) cells. The analyses show that group III has the highest expression, with 75.0% of DRG cells expressing mGluR8, followed by group II, with 51.6% expressing mGluR2/3, followed by group I, with only 6.8% expressing mGluR1alpha. mGluR8 is expressed by small, medium, and large diameter cells. In contrast, mGluR1alpha and mGluR2/3 are expressed by mainly small and medium cells. Approximately half of cells expressing group I mGluR1alpha also express either group II mGluR2/3 or group III mGluR8. These mGluR1alpha double-labeled populations are not likely to overlap since >1.0% of mGluR1alpha are triple-labeled. As expected from the high percentage of single-labeled mGluR2/3 and mGluR8 cells, there is a considerable population of double-labeled cells with approximately 30% of each population expressing both receptors. Due to the fact that the number of mGluR1alpha-expressing cells in the DRG is low, the percentage of triple-labeled cells is also low ( approximately 1-2%). The prevalence of groups II and III indicate that glutamate could have a substantial inhibitory effect of primary afferent function, reducing and/or fine-tuning sensory input before transmission to the spinal cord. These anatomical data highlight the potential inhibitory role glutamate may play in peripheral sensory transmission.     

Characterization of modulatory effects of postsynaptic metabotropic glutamate receptors on calcium currents in rat nucleus tractus solitarius

It is well known that metabotropic glutamate receptors (mGluRs) have multiple actions on neuronal excitability mediated by G-protein-coupled receptors, although the exact mechanisms by which these actions occur are not understood. This study examines the effects of mGluRs agonists on voltage-dependent Ca2+ channels (VDCCs) currents (ICa) in the nucleus tractus solitarius (NTS) of rats using patch-clamp recording methods. An application of (RS)-3,5-dihydroxyphenylglycine (DHPG, Group I mGluR agonist) caused both facilitation and inhibition of L-type and N/P/Q-types ICa, respectively. Neither (2S, 2'R, 3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine (DCG, Group II mGluRs agonist) nor L-(+)-2-amino-4-phosphonobutyric acid (AP-4, Group III mGluRs agonist) nor (RS)-2-chloro-5-hydroxyphenylglycine (CHPG, mGluR5 agonist) modulated ICa. Intracellular dialysis of the Gq/11-protein antibody and Gi-protein antibody attenuated the DHPG-induced facilitation and inhibition, respectively. The phospholipase C (PLC) inhibitor, as well as inhibition of either the protein kinase C (PKC) or inositol-1,4,5-trisphosphate (IP3) attenuated the DHPG-induced facilitation of ICa but not a DHPG-induced inhibition. Application of a strong depolarizing voltage prepulse attenuated the DHPG-induced inhibition of ICa. These results indicate that mGluR1 facilitates L-type VDCCs via Gq/11-protein involving PKC including IP3 formation. On the other hand, mGluR1 inhibits N- and P/Q-types VDCCs via Gi-protein betagamma subunits.     

Metabotropic glutamate receptor 5 activation inhibits microglial associated inflammation and neurotoxicity

The Group I metabotropic glutamate receptor 5 (mGluR5) can modulate addiction, pain, and neuronal cell death. Expression of some mGluRs, such as Group II and III mGluRs, has been reported in microglia and may affect their activation. However, the expression and role of mGluR5 in microglia is unclear. Using immunocytochemistry and Western blot, we demonstrate that mGluR5 protein is expressed in primary microglial cultures. Activation of mGluR5 using the selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) significantly reduces microglial activation in response to lipopolysaccharide, as indicated by a reduction in nitric oxide, reactive oxygen species, and TNFalpha production. Microglial induced neurotoxicity is also markedly reduced by CHPG treatment. The anti-inflammatory effects of CHPG are not observed in microglial cultures from mGluR5 knockout mice and are blocked by selective mGluR5 antagonists, suggesting that these actions are mediated by the mGluR5 receptor. Anti-inflammatory actions of mGluR5 activation are attenuated by phospholipase C and protein kinase C inhibitors, as well as by calcium chelators, suggesting that the mGluR5 activation in microglia involves the G(alphaq)-protein signal transduction pathway. These data indicate that microglial mGluR5 may represent a novel target for modulating neuroinflammation, an important component of both acute and chronic neurodegenerative disorders.     

Seizures and neuronal damage induced in the rat by activation of group I metabotropic glutamate receptors with their selective agonist 3,5-dihydroxyphenylglycine

While it is well documented that the overactivation of ionotropic glutamate receptors leads to seizures and excitotoxic injury, little is known about the role of metabotropic glutamate receptors (mGluRs) in epileptogenesis and neuronal injury. Intracerebroventricular (i.c.v.) infusion of the group I mGluR specific agonist (R,S)-3,5-dihydroxyphenylglycine (3,5-DHPG) (1.5 μmol) to conscious rats produced severe and delayed seizures (onset at 4 hr) in 70% of the animals. The i.c.v. infusion of the group I mGluR non-selective agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (2 μmol) produced a similar rate of severe seizures, but with an early onset (0.6 hr). The analysis of motor activity showed that 3,5-DHPG elicited higher central stimulatory action than did 1S,3R-ACPD. Histopathological analysis of the hippocampus showed that 3,5-DHPG produced severe neuronal damage mainly in the CA1 pyramidal neurons and, to a lesser extent, in the CA3. Although 1S,3R-ACPD infusion also induced a slight injury of the CA1 and CA3 pyramidal neurons, damage was greater in the CA4 and dentate gyrus cells. In conclusion, the in vivo activation of group I mGluRs with the selective agonist 3,5-DHPG produces hyperexcitatory effects that lead to seizures and neuronal damage, these effects being more severe than those observed after infusion of the non-selective agonist 1S,3R-ACPD. J. Neurosci. Res. 51:339–348, 1998. © 1998 Wiley-Liss, Inc.     

Metabotropic glutamate receptors as targets for multipotential treatment of neurological disorders

Glutamate is a major excitatory neurotransmitter in the CNS that is involved in numerous cellular functions, including cell death and survival. Metabotropic glutamate receptors (mGluR) are G-protein coupled receptors that have been classified into three groups on the basis of signal transduction pathways and pharmacological profiles. Group I, II, and III mGluRs are found on cell types within and peripheral to the CNS, including neurons, microglia, astrocytes, oligodendrocytes, T- and B-cell lymphocytes, osteoblasts, hepatocytes, and endothelial cells, among others. These receptors have a number of effects on cells that can influence outcome after trauma, including reducing neuronal and oligodendroglial cell death, inflammation, and endothelial permeability. Thus, mGluRs are a promising multipotential therapeutic approach. Because the pathology of CNS trauma and neurodegeneration is multifactorial (including, for example, oxidative stress, mitochondrial breakdown, and inflammation), therapies that serve to modulate multiple pathophysiological pathways may prove more effective than those directed at a single target. This review examines the multipotential therapeutic utility of mGluR modulation in acute and chronic injury and neurodegeneration.