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.     

Upregulation of Group I metabotropic glutamate receptors in neurons and astrocytes in the dorsal horn following spinal cord injury

Of the glutamate receptor types, the metabotropic glutamate receptors (mGluRs) are G proteins coupled and can initiate a number of intracellular pathways leading to hyperexcitability of spinal neurons. In this study, we tested the expression of mGluRs to determine which cell types might contribute to sustained neuronal hyperexcitability in the lumbar enlargement with postoperative day (POD) 7 (early), 14 (late), and 30 (chronic phase) following spinal cord injury (SCI) by unilateral hemisection at T13 in Sprague-Dawley rats. Expression was determined by confocal analyses of immunocytochemical reaction product of neurons (NeuN positive) and astrocytes (GFAP positive) in the dorsal horn on both sides of the L4 segment. Neurons were divided into two sizes: small (<20 microm) and large (>35 microm), for physiological reasons. We report a significant increase of mGluR(1) expression in large and small neurons of the dorsal horn on both sides of the cord in late and chronic phases when compared to control sham groups. Expression of mGluR(2/3) significantly increased in large neurons on the ipsilateral (hemisected) side in the late phase. Expression of mGluR(5) significantly increased in large neurons in early, late, and chronic phases. In addition, mGluR(1) and mGluR(5) expression after hemisection was significantly increased in astrocytes in early, late, and chronic phases; whereas mGluR(2/3) did not display any significant changes. In conclusion, our data demonstrate long-term changes in expression levels of Group I mGluRs (mGluR(1) and mGluR(5)) in both neurons and astrocytes in segments below a unilateral SCI. Thus, permanent alterations in dorsal horn receptor expression may play important roles in transmission of nociceptive responses in the spinal cord following SCI.     

AIDA reduces glutamate release and attenuates mechanical allodynia after spinal cord injury

Spinal cord injury (SCI) leads to an increase in extracellular excitatory amino acid (EAA) concentrations, resulting in glutamate receptor-mediated excitotoxicity and central sensitization. To test contributions of group I metabotropic glutamate receptors (mGluRs) in SCI induced release of glutamate and in behavioral outcomes of central sensitization following injury, we administered 1-aminoindan-1,5-dicarboxylic acid (AIDA; 0.1 nmol intraspinally), a potent group I mGluR antagonist, to rats immediately after spinal cord contusion injury. EAAs were collected by microdialysis and quantified using HPLC. AIDA significantly decreased extracellular glutamate but not aspartate concentrations and significantly attenuated the development of mechanical but not thermal allodynia. These results suggest mGluRs play an important role in injury-induced EAA release and in central sensitization following SCI.     

Plasticity-dependent changes in metabotropic glutamate receptor expression at excitatory hippocampal synapses

Group I metabotropic glutamate receptors, mGluR1 and mGluR5, modulate NMDA receptor-mediated synaptic transmission and plasticity and mediate mGluR-dependent plasticity. Here we report that the synaptic expression of mGluRs can be regulated by NMDA receptor-dependent synaptic plasticity, but that this is dependent on the subtype of mGluR. Silent synapses, but not active synapses, were found to lack Group I mGluRs showing that mGluRs must be inserted into synapses after they are unsilenced. The induction of LTP resulted in an increased synaptic expression of mGluR1 in an NMDA receptor-dependent manner. mGluR1 is internalized from synapses via NMDA receptor-dependent LTD. Interestingly we found no evidence for the regulation of mGluR5 by NMDA receptor-dependent plasticity. This regulation of Group I mGluRs will determine the ability of synapses to undergo mGluR-dependent modulation of synaptic transmission and plasticity, providing a mechanism for metaplasticity and state-dependent plasticity at hippocampal synapses.     

Rapid changes in expression of glutamate transporters after spinal cord injury

Glutamate is a major excitatory neurotransmitter in the mammalian CNS. After its release, specific transporter proteins rapidly remove extracellular glutamate from the synaptic cleft. The clearance of excess extracellular glutamate prevents accumulation under normal conditions; however, CNS injury elevates extracellular glutamate concentrations to neurotoxic levels. The purpose of this study was to examine changes in expression and in spatial localization of glial glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2) and the neuronal glutamate transporter EAAC1 (EAAT3) after spinal cord contusion injury (SCI). The levels of all three transporters significantly increased at the epicenter of injury (T10) and in segments rostral and caudal to the epicenter as determined by Western blot analysis. Quantitative immunohistochemistry demonstrated an increase in GLAST staining in laminae I-V and lamina X both rostral and caudal to the epicenter of injury. Staining for GLT-1 increased significantly in lamina I rostral to the injury site and in the entire gray matter caudal to the injury site. A significant increase in EAAC1 staining was observed in laminae I-IV rostral to the epicenter of injury and throughout the gray matter caudal to the injury site. The results suggest that upregulation of these high affinity transporters occurs rapidly and is important in regulating glutamate homeostasis after SCI.     

mGluRs: a target for pharmacotherapy in Parkinson disease

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled excitatory amino acid (glutamate) receptors and are abundantly expressed in basal ganglia nuclei. We used behavioral, regional glucose uptake metabolic mapping, and FOS protein expression to examine the effects of stimulating striatal and subthalamic mGluRs in rats. Stimulation of striatal Group I mGluRs produced behavioral effects mediated by polysynaptic activation of subthalamic neurons. Stimulation of subthalamic Group II mGluRs produced similar effects. Excessive activity of subthalamic neurons is a key feature of parkinsonism. mGluR Group I or Group II antagonists may prove to be useful for symptomatic treatment of parkinsonism. Stimulation of Group III mGluRs produced behavioral effects in only 6-hydroxydopamine-lesioned animals. Regional glucose uptake metabolic mapping and FOS expression studies suggested that striatal dopamine denervation produced increased sensitivity of Group III mGluRs. Agents active at Group III mGluRs may also be useful for treatment of parkinsonism.     

Preproenkephalin mRNA expression in rat dorsal striatum induced by selective activation of metabotropic glutamate receptor subtype-5

Group I metabotropic glutamate receptors (mGluR1 and mGluR5 subtypes) are positively coupled to phosphoinositide hydrolysis through G-proteins and are densely expressed in medium-sized projection neurons of striatum. Selective activation of Group I mGluRs upregulates preproenkephalin (PPE) mRNA expression in the rat dorsal striatum. This study investigated the role of one subtype of Group I receptors, mGluR5, in the regulation of PPE mRNA expression in the rat dorsal striatum using quantitative in situ hybridization. Unilateral injection of the mGluR5 selective agonist (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG) into the dorsal striatum (caudoputamen) of chronically cannulated rats at doses of 50 and 200 nmol elevated basal levels of PPE mRNA in the injected dorsal striatum. The induction of PPE mRNA was evident at 1 h, remained at 3 h, and returned to normal level 6 h after CHPG injection. Pretreatment with an mGluR5 selective antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) at a dose of 10 mg/kg (i.p.) blocked CHPG-stimulated PPE expression. MPEP also attenuated PPE expression induced by dopamine D(2) receptor blockade with eticlopride (0.5 mg/kg, i.p.). Administration of MPEP alone had no significant effects on basal levels of PPE mRNA in the striatum. The results from the present study demonstrate that glutamatergic tone on mGluR5 possesses the ability to positively regulate PPE gene expression in striatal neurons in vivo. Moreover, activation of mGluR5 participates in the mediation of D(2) antagonist-induced PPE expression.     

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.     

Distinct regulation of metabotropic glutamate receptor (mGluR1 alpha) in the developing limbic system following multiple early-life seizures

The effects of repeated neonatal seizures on metabotropic glutamate receptors (mGluRs) during critical periods of brain development are unknown. Therefore, we characterized the expression of Group I (mGluR1 and mGluR5) and Group II (mGluR2/3) metabotropic glutamate receptor proteins in the developing limbic system in response to a varied neonatal seizure history. Status epilepticus was induced with kainic acid (KA) either once (1x KA) on postnatal (P) day (P13), twice (2x KA) on P6 and P9 or P13, or three times (3x KA) on P6, P9, and P13. In control hippocampus, mGluR1alpha protein expression differed at all stages of development examined, whereas mGluR2/3 and mGluR5 protein expression patterns were mature by P15. After KA-induced status epilepticus, there was a significant elevation in mGluR1alpha protein expression within a select group of inhibitory interneurons of the CA1 stratum oriens-alveus that was enhanced with increasing number of neonatal seizures. mGluR2/3 and mGluR5 subtypes were unchanged. Increases were also observed within neurons of the amygdala and piriform cortex. Selective increases of mGluR1alpha subtypes within limbic structures may contribute to the resistance and tolerance of the immature hippocampus from damage. This may occur by excessive stimulation of excitatory synapses to collectively enhance the inhibitory drive of the immature brain by increasing GABA release. Data suggest that the mGluR1alpha subtype plays an important role in regulating hippocampal network activity after early-life seizures.     

Chronic pain after clip-compression injury of the rat spinal cord

Chronic tactile allodynia and hyperalgesia are frequent complications of spinal cord injury (SCI) with poorly understood mechanisms. Possible causes are plastic changes in the central arbors of nociceptive and nonnociceptive primary sensory neurons and changes in descending modulatory serotonergic pathways. A clinically relevant clip-compression model of SCI in the rat was used to investigate putative mechanisms of chronic pain. Behavioral testing (n = 18 rats) demonstrated that moderate (35 g) or severe (50 g) SCI at the 12th thoracic spinal segment (T-12) reliably produces chronic tactile allodynia and hyperalgesia that can be evoked from the hindpaws and back. Quantitative morphometry (n = 37) revealed no changes after SCI in the density or distribution of Abeta-, Adelta-, and C-fiber central arbors of primary sensory neurons within the thoracolumbar segments T-6 to L-4. This observation rules out a mandatory relationship between pain-related behaviors and changes in the distribution or density of central afferent arbors. The area of serotonin immunoreactivity in the dorsal horn (n = 12) decreased caudal to the injury site (L1-4) and increased threefold rostral to it (T9-11). The decreased serotonin and presence of tactile allodynia and hyperalgesia caudal to the injury are consistent with disruption of descending antinociceptive serotonergic tracts that modulate pain transmission. The functional significance of the increased serotonin in rostral segments may relate to the development of tactile allodynia as serotonin also has known pronociceptive actions. Changes in the descending serotonergic pathway require further investigation, as a disruption of the balance of serotonergic input rostral and caudal to the injury site may contribute to the etiology of chronic pain after SCI.     

Modulation of calcium channels by group I and group II metabotropic glutamate receptors in dentate gyrus neurons from patients with temporal lobe epilepsy

PURPOSE: Metabotropic glutamate receptors (mGluRs) might be promising new drug targets for the treatment of epilepsy because the expression of certain mGluRs is regulated in epilepsy and because activation of mGluRs results in distinctive anti- and proconvulsant effects. Therefore, we examined how mGluR activation modulates high-voltage-activated (HVA) Ca2+ channels. METHODS: Whole-cell patch-clamp recordings were obtained from granule cells and interneuron-like cells acutely isolated from the dentate gyrus of patients with pharmacoresistent temporal lobe epilepsy. RESULTS: Agonists selective for either group I or group II mGluRs rapidly and reversibly reduced HVA currents in most dentate gyrus cells. These modulatory effects were inhibited by the respective group I and group II mGluR antagonists. The specific Ca2+ channel antagonists nifedipine and omega-conotoxin GVIA potently occluded the effects of group I and II mGluR agonists, respectively, indicating that group I mGluRs acted on L-type channels and group II mGluRs affected N-type channels. About two thirds of the responsive neurons were sensitive either to group I or group II mGluRs, whereas a minority of cells showed effects to agonists of both groups, indicating a variable mGluR expression pattern. CONCLUSIONS: Group I and group II mGluRs are expressed in human dentate gyrus neurons and modulate L- and N-type HVA channels, respectively. The data shed light on the possible cellular sequelae of the mGluR1 upregulation observed in human epileptic dentate gyrus as well as on possible mGluR-mediated anticonvulsant mechanisms.     

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.     

Down-regulation of metabotropic glutamate receptor 1alpha in globus pallidus and substantia nigra of parkinsonian monkeys

Enhanced glutamatergic neurotransmission via the subthalamopallidal or subthalamonigral projection seems crucial for developing parkinsonian motor signs. In the present study, the possible changes in the expression of metabotropic glutamate receptors (mGluRs) were examined in the basal ganglia of a primate model for Parkinson's disease. When the patterns of immunohistochemical localization of mGluRs in monkeys administered systemically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were analysed in comparison with normal controls, we found that expression of mGluR1alpha, but not of other subtypes, was significantly reduced in the internal and external segments of the globus pallidus and the substantia nigra pars reticulata. To elucidate the functional role of mGluR1 in the control of pallidal neuron activity, extracellular unit recordings combined with intrapallidal microinjections of mGluR1-related agents were then performed in normal and parkinsonian monkeys. In normal awake conditions, the spontaneous firing rates of neurons in the pallidal complex were increased by DHPG, a selective agonist of group I mGluRs, whereas they were decreased by AIDA, a selective antagonist of group I mGluRs, or LY367385, a selective antagonist of mGluR1. These electrophysiological data strongly indicate that the excitatory mechanism of pallidal neurons by glutamate is mediated at least partly through mGluR1. The effects of the mGluR1-related agents on neuronal firing in the internal pallidal segment became rather obscure after MPTP treatment. Our results suggest that the specific down-regulation of pallidal and nigral mGluR1alpha in the parkinsonian state may exert a compensatory action to reverse the overactivity of the subthalamic nucleus-derived glutamatergic input that is generated in the disease.     

Differential expression of group I metabotropic glutamate receptors in rat spinal cord somatic and autonomic motoneurons: possible implications for the pathogenesis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of somatic, but not autonomic, motoneurons. The reason for this selective vulnerability is unknown. The pathogenesis of ALS is thought to involve glutamatergic excitotoxic mechanisms. While overactivation of ionotropic glutamate receptors may trigger excitotoxicity, we have previously shown that stimulation of group I metabotropic glutamate receptors (mGluRs) can exert neuroprotective effects on cultured motoneurons. Using in situ hybridization, we found a differential expression of group I mGluRs (mGluR1 and 5) in rat spinal cord. Autonomic motoneurons from the sacral parasympathetic Onuf's nucleus and thoracic sympathetic neurons, which are spared in ALS, express high levels of mGluR5, while somatic motoneurons do not. In addition, mGluR1 mRNA is found only in smaller somatic motoneurons, which seem to be less vulnerable in ALS. Thus, differential mGluR expression might provide a possible clue to the selective vulnerability of different motoneuronal subpopulations in ALS.     

Expression and functional properties of group I metabotropic glutamate receptors in bovine chromaffin cells

We demonstrate the presence and functional properties of Group I metabotropic glutamate receptors (mGluRs) expressed in chromaffin cells. Immunocytochemical techniques revealed that two mGluR subtypes (mGluR1alpha and mGluR5) are expressed in chromaffin cells, located in both the cytoplasmic membrane and the cytosol surrounding the nucleus. These mGluRs are functionally active on catecholamine (CA) secretion in chromaffin cells because both (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) and the specific agonist of Group I mGluRs, (S)-3,5-dihydroxyphenylglycine (DHPG), were able to stimulate the release of CAs (adrenaline and noradrenaline) in a dose-response manner. These effects were specifically reversed by L-(+)-2-amino-3-phosphonopropionic acid (L-AP3), a selective antagonist of the Group I metabotropic glutamate receptors. t-ACPD induced an increase in CA secretion in both the presence and absence of extracellular calcium, the former effect being accompanied by cell membrane depolarization. Noradrenaline (NA) release was higher in the presence of extracellular calcium than in its absence, whereas adrenaline release was of the same order under both conditions. These results indicate that different subtypes of Group I mGluRs are present in noradrenergic and adrenergic cells. Fluorescence imaging techniques in single cells showed different t-ACPD-induced increases in intracellular calcium in different chromaffin cells: in chromaffin cells, 67% expressed functional metabotropic glutamate receptors and with nicotinic receptors, whereas the remaining 33% expressed only nicotinic receptors. In the absence of external calcium, only about 25% of cells responded to t-ACPD-increased intracellular calcium by increasing inositol 1,4,5-trisphosphate (IP(3)) concentration and subsequent calcium mobilization from intracellular stores, whereas the remaining 75% increased intracellular calcium by promoting Ca(2+) influx from the extracellular medium through L- and N- but not P/Q voltage-dependent calcium channels.     

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.     

Immortalized Hypothalamic Neurons Express Metabotropic Glutamate Receptors Positively Coupled to Cyclic AMP Formation

We have characterized the expression pattern and pharmacological profile of activation of metabotropic glutamate receptors (mGluRs) in immortalized, gonadotropin releasing hormone (GnRH)-secreting GT1-7 cells, which represent a homogeneous cellular population of hypothalamic origin. These cells are known to respond to the mGluR agonist (1S, 3R)-cyclopentanedicarboxylic acid (1S, 3R-ACPD) with increased GnRH release. To establish which specific mGluR subtypes are expressed by GT1-7 cells, we used polyclonal antibodies raised against non-conserved regions of the carboxy-terminal domains of individual subtypes. The selectivity of these antibodies was tested in HEK 293 cells transiently transfected with each mGluR subtype. GTl-7 cells stained positively for the subtypes mGluRla, -1b and -5 (belonging to group I mGluRs), mGluR2/3 (group 11) and mGluR7 (group 111). Agonists of group I mGluRs, including 1S, 3R-ACPD, activated phosphoinositide hydrolysis in GT1-7 cells. This effect, however, was manifested only when cell density was low, and it disappeared when cells reached confluence. Stimulation of phosphoinositide hydrolysis could not therefore have been related to hormone secretion because 1S, 3RACPD effectively released GnRH in confluent cultures. We then focused on group II and Ill mGluRs, which in transfected cells are negatively linked to adenylate cyclase activity. Unexpectedly, however, agonists which preferentially activate group II and Ill mGluRs increased both basal and forskolin-stimulated cAMP accumulation in GT1-7 cells. Stimulation of GAMP accumulation by mGluR agonists was not prevented by enzymatic depletion of endogenous adenosine, but was obliterated when cells were incubated with agonists of receptors positively coupled to adenylate cyclase, such as P-adrenergic and prostaglandin E2 receptors. These results suggest that GT1-7 cells express a novel mGluR subtype positively coupled to adenylate cyclase, which shares the same transduction pathway of other classical receptors coupled with a G,-type of GTP-binding protein.     

Interaction between metabotropic and ionotropic glutamate receptors regulates neuronal network activity.

Experimental and computational techniques have been used to investigate the group I metabotropic glutamate receptor (mGluR)-mediated increase in the frequency of spinal cord network activity underlying locomotion in the lamprey. Group I mGluR activation potentiated the amplitude of NMDA-induced currents in identified motoneurons and crossed caudally projecting network interneurons. Group I mGluRs also potentiated NMDA-induced calcium responses. This effect was blocked by a group I mGluR-specific antagonist, but not by blockers of protein kinase A, C, or G. The effect of group I mGluRs activation was also tested on NMDA-induced oscillations known to occur during fictive locomotion. Activation of these receptors increased the duration of the plateau phase and decreased the duration of the hyperpolarizing phase. These effects were blocked by a group I mGluR antagonist. To determine its role in the modulation of NMDA-induced oscillations and the locomotor burst frequency, the potentiation of NMDA receptors by mGluRs was simulated using computational techniques. Simulating the interaction between these receptors reproduced the modulation of the plateau and hyperpolarized phases of NMDA-induced oscillations, and the increase in the frequency of the locomotor rhythm. Our results thus show a postsynaptic interaction between group I mGluRs and NMDA receptors in lamprey spinal cord neurons, which can account for the regulation of the locomotor network output by mGluRs.