Differential effects of N-acetyl-aspartyl-glutamate on synaptic and extrasynaptic NMDA receptors are subunit- and pH-dependent in the CA1 region of the mouse hippocampus

Khacho, Pamela; Wang, Boyang; Ahlskog, Nina; Hristova, Elitza; Bergeron, Richard

doi:10.1016/j.nbd.2015.08.017

Cited by 27 publications

(17 citation statements)

References 81 publications

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“…Inhibition of GCPII could provide neuroprotective effects against excitotoxicity by reducing the production of extracellular glutamate (Slusher et al, 1999) both by decreasing liberation of glutamate from NAAG and by increasing NAAG concentrations which activates mGluR3 (Neale, 2011) and decreases presynaptic glutamate release (Wroblewska et al, 1997, Bruno et al, 1998b, Zuo et al, 2012). NAAG has also been shown to prevent NMDA-induced neuronal death (Puttfarcken et al, 1993, Valivullah et al, 1994, Khacho et al, 2015), and induce TGF-β release via activation of Mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K) (Bruno et al, 1998a, D’Onofrio et al, 2001). This may explain the neuroprotective effects of GCPII inhibition and NAAG administration in several adult models of neuroinflammation (Ghadge et al, 2003, Thomas et al, 2003, Rahn et al, 2012) and in hypoxic-ischemia (Slusher et al, 1999, Cai et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Maternal inflammation leads to impaired glutamate homeostasis and up-regulation of glutamate carboxypeptidase II in activated microglia in the fetal/newborn rabbit brain

Zhi¹,

Bassam²,

Thomas

et al. 2016

Neurobiology of Disease

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Astrocyte dysfunction and excessive activation of glutamatergic systems has been implicated in a number of neurologic disorders, including periventricular leukomalacia (PVL) and cerebral palsy (CP). However, the role of chorioamnionitis on glutamate homeostasis in the fetal and neonatal brains is not clearly understood. We have previously shown that intrauterine endotoxin administration results in intense microglial ‘activation’ and increased pro-inflammatory cytokines in the periventricular region (PVR) of the neonatal rabbit brain. In this study, we assessed the effect of maternal inflammation on key components of the glutamate pathway and its relationship to astrocyte and microglial activation in the fetal and neonatal New Zealand white rabbit brain. We found that intrauterine endotoxin exposure at gestational day 28 (G28) induced acute and prolonged glutamate elevation in the PVR of fetal (G29, 1 day post-injury) and postnatal day 1 (PND1, 3 days post-injury) brains along with prominent morphological changes in the astrocytes (soma hypertrophy and retracted processes) in the white matter tracts. There was a significant increase in glutaminase and N-Methyl-D-Aspartate receptor (NMDAR) NR2 subunits expression along with decreased glial L-glutamate transporter 1 (GLT1) in the PVR at G29, that would promote acute dysregulation of glutamate homeostasis. This was accompanied with significantly decreased TGF-β1 at PND1 in CP kits indicating ongoing neuroinflammation. We also show for the first time that glutamate carboxypeptidase II (GCPII) was significantly increased in the activated microglia at the periventricular white matter area in both G29 and PND1 CP kits. This was confirmed by in vitro studies demonstrating that LPS activated primary microglia markedly upregulate GCPII enzymatic activity. These results suggest that maternal intrauterine endotoxin exposure results in early onset and long-lasting dysregulation of glutamate homeostasis, which may be mediated by impaired astrocyte function and GCPII upregulation in activated microglia.

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Section: Discussionmentioning

confidence: 99%

Maternal inflammation leads to impaired glutamate homeostasis and up-regulation of glutamate carboxypeptidase II in activated microglia in the fetal/newborn rabbit brain

Zhi¹,

Bassam²,

Thomas

et al. 2016

Neurobiology of Disease

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“…With respect to enzymatic mechanism, to date there are 3 known FOLH1 /GCPII substrates that could be implicated as possible mediators of the therapeutic effect, including N-acetylaspartylglutamate (NAAG) (28), folate polyglutamate (29–31), and laminin-derived peptides (32, 33). NAAG is one of the most abundant peptides in nervous tissues where it is thought to participate in glutamatergic transmission, acting through NMDA and mGlu3 receptors (20, 34, 35). Although little is known about NAAG in the enteric nervous system, its receptors have been reported in the gut (36).…”

Section: Discussionmentioning

confidence: 99%

FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities

Rais¹,

Jiang²,

Zhai³

et al. 2016

JCI Insight

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Recent gene-profiling analyses showed significant upregulation of the folate hydrolase (FOLH1) gene in the affected intestinal mucosa of patients with inflammatory bowel disease (IBD). The FOLH1 gene encodes a type II transmembrane glycoprotein termed glutamate carboxypeptidase II (GCPII). To establish that the previously reported increased gene expression was functional, we quantified the glutamate carboxypeptidase enzymatic activity in 31 surgical specimens and report a robust 2.8- to 41-fold increase in enzymatic activity in the affected intestinal mucosa of IBD patients compared with an uninvolved area in the same patients or intestinal mucosa from healthy controls. Using a human-to-mouse approach, we next showed a similar enzymatic increase in two well-validated IBD murine models and evaluated the therapeutic effect of the potent FOLH1/ GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) (IC50 = 300 pM). In the dextran sodium sulfate (DSS) colitis model, 2-PMPA inhibited the GCPII activity in the colonic mucosa by over 90% and substantially reduced the disease activity. The significance of the target was confirmed in FOLH1−/− mice who exhibited resistance to DSS treatment. In the murine IL-10−/− model of spontaneous colitis, daily 2-PMPA treatment also significantly reduced both macroscopic and microscopic disease severity. These results provide the first evidence of FOLH1/GCPII enzymatic inhibition as a therapeutic option for IBD.

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“…NAAG, present in neurons and glia, is a neuromodulatory peptide that acts as an agonist at mGluR3 receptors to decrease neurotransmitter release (see Neale et al 2011). NAAG can also act as a NMDA receptor antagonist (Bergeron et al 2007) or agonist (Westbrook et al 1986) depending on the cellular environment and subunit composition of the NMDA receptors, among other factors (Khacho et al 2015). Compounds that increase NAAG, such as NAAG peptidase inhibitors, may have therapeutic effects that may be associated with mGluR2/3 agonism, including antipsychotic effects (Olszewski et al 2004) or decreasing additive behaviours (Xi et al 2010a, b).…”

Section: H-mrs Metabolites Involved In Excitatory and Inhibitory Neurmentioning

confidence: 99%

The potential of 1H-MRS in CNS drug development

Egerton

2019

Psychopharmacology

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Rationale Proton magnetic resonance spectroscopy (1 H-MRS) is a cross-species neuroimaging technique that can measure concentrations of several brain metabolites, including glutamate and GABA. This non-invasive method has promise in developing centrally acting drugs, as it can be performed repeatedly within-subjects and be used to translate findings from the preclinical to clinical laboratory using the same imaging biomarker. Objectives This review focuses on the utility of single-voxel 1 H-MRS in developing novel glutamatergic or GABAergic drugs for the treatment of psychiatric disorders and includes research performed in rodent models, healthy volunteers and patient cohorts. Results Overall, these studies indicate that 1 H-MRS is able to detect the predicted pharmacological effects of glutamatergic or GABAergic drugs on voxel glutamate or GABA concentrations, although there is a shortage of studies examining dose-related effects. Clinical studies have applied 1 H-MRS to better understand drug therapeutic mechanisms, including the glutamatergic effects of ketamine in depression and of acamprosate in alcohol dependence. There is an emerging interest in identifying patient subgroups with 'high' or 'low' brain regional 1 H-MRS glutamate levels for more targeted drug development, which may require ancillary biomarkers to improve the accuracy of subgroup discrimination. Conclusions Considerations for future research include the sensitivity of single-voxel 1 H-MRS in detecting drug effects, inter-site measurement reliability and the interpretation of drug-induced changes in 1 H-MRS metabolites relative to the known pharmacological molecular mechanisms. Ongoing technological development, in single-voxel 1 H-MRS and in related complementary techniques, will further support applications within CNS drug discovery.

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Differential effects of N-acetyl-aspartyl-glutamate on synaptic and extrasynaptic NMDA receptors are subunit- and pH-dependent in the CA1 region of the mouse hippocampus

Cited by 27 publications

References 81 publications

Maternal inflammation leads to impaired glutamate homeostasis and up-regulation of glutamate carboxypeptidase II in activated microglia in the fetal/newborn rabbit brain

Maternal inflammation leads to impaired glutamate homeostasis and up-regulation of glutamate carboxypeptidase II in activated microglia in the fetal/newborn rabbit brain

FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities

The potential of 1H-MRS in CNS drug development

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