Decreased levels of d-aspartate and NMDA in the prefrontal cortex and striatum of patients with schizophrenia

Errico, Francesco; Napolitano, Francesco; Squillace, Marta; Vitucci, Daniela; Blasi, Giuseppe; Bartolomeis, Andrea de; Bertolino, Alessandro; D’Aniello, Antimo; Usiello, Alessandro

doi:10.1016/j.jpsychires.2013.06.013

Cited by 86 publications

(94 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Patients with schizophrenia have a reduced level of NMDA receptor subunits in the PFC, including the dlPFC (Errico et al 2013;Dean et al 2016). Further, levels of endogenous NMDA receptor agonists are also reduced in patients with schizophrenia and nonmedicated patients exhibit reduced NMDA receptor binding compared to healthy controls (Pilowsky et al 2006;Errico et al 2013).…”

Section: Glutamate and Nmda Receptor Dysfunction In Schizophreniamentioning

confidence: 99%

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

View full text Add to dashboard Cite

The cognitive symptoms observed in schizophrenia are highly prevalent and predictive of patient functional outcome but are not usually alleviated by conventional antipsychotics. In a recent pilot study, sodium nitroprusside (SNP), a nitric oxide donor, was identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients.Adjunctive SNP has also been reported to decrease the positive and negative symptoms experienced by patients for weeks following a single administration. The mechanisms underlying these changes and the areas of cognition affected remain largely unknown.Therefore, it is of interest to examine the effects of SNP using a rodent model of schizophrenia that has demonstrated predictive validity. The aim of the present experiment was to explore the effects of SNP on the acute MK-801 rodent model of schizophrenia using a highly translatable task in order to establish its validity. Working memory and pattern separation were measured using the trial-unique, delayed nonmatching-to-location (TUNL) task in touchscreen-equipped operant conditioning chambers. Acute MK-801 administration 25 minutes prior to task initiation impaired both areas of cognition. When SNP and MK-801 were administered within 5 minutes of each other, no interaction was observed. Interestingly, SNP improved performance on trials with difficult to discriminate patterns (p=0.058). Previous rodent studies using the ketamine model of schizophrenia and the novel object preference task observed a preventative effect of SNP administration. When we administered SNP nearly 4 hours prior to MK-801, no cognitive improvements were observed. Our results suggest that SNP may have intrinsic cognitive enhancing properties but is not capable of reducing MK-801-induced working memory and pattern separation impairments in the TUNL task. This study failed to mirror the results of the human pilot study that observed improved working memory following SNP administration.iii Further, it did not replicate previous animal studies using ketamine. Ultimately, the findings suggest that the effects of MK-801 in the TUNL task may not hold the predictive validity needed for its use in the study of SNP. In order to advance the understanding of SNP, future studies should investigate other translatable paradigms to establish validity. iv ACKNOWLDGEMENTSFirst and foremost, I would like to thank my supervisor Dr. John Howland, for his guidance and encouragement over the past three years. He believed in my abilities before I had proven them to myself and pushed me to be the best scientist and student I could be. John has provided me with countless opportunities to grow as a researcher and selflessly helped me make decisions about my future. I would not be where I am today without him and will always be grateful to have had such an incredible mentor in my life.I would like to thank my committee members, Dr.

show abstract

Section: Glutamate and Nmda Receptor Dysfunction In Schizophreniamentioning

confidence: 99%

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Reduced NMDA-R expression in several brain regions, including the frontal cortex and hippocampus, has been found in individuals with schizophrenia (Errico et al, 2013;Geddes et al, 2014Geddes et al, , 2011Weickert et al, 2013). GABAA-R expression level differences vary between receptor subtypes and brain regions in individuals with schizophrenia (Benes et al, 1996a(Benes et al, , 1996bDuncan et al, 2010).…”

Section: The Two-hit Nrg1-pcp Model Shows Reduced Nmda-r and Gabaa-r mentioning

confidence: 99%

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

et al. 2016

View full text Add to dashboard Cite

Rationale An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. Objectives We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-daspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a twohit mouse model of schizophrenia. Methods Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. Results In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. Conclusions We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3. Disciplines Medicine and Health Sciences Publication DetailsEngel, M., Snikeris, P., Matosin, N., Newell, K. Anne., Huang, X. & Frank, E. (2016). mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia. Psychopharmacology, 233 (8) AcknowledgmentsThis work was supported by the Schizophrenia Research Institute, utilising infrastructure funding from the NSW Ministry of Health. LY379268 was kindly gifted by Eli Lilly & Co (Indianapolis, USA). The funding bodies had no role in the study design, data collection and publication decisions. 2 AbstractRationale An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of Group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored.Objectives We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia.Me...

show abstract

“…24,25 In conclusion, our data suggest that increased expression of DDO mRNA in the PFC of SCZ patients can result in a corresponding excessive degradation of D-Asp. 23 We also demonstrate in a preclinical model that constitutive high levels of D-Asp exert a putative protective effect against the SCZ-like symptoms induced by the NMDAR antagonist PCP. Taken together, these findings support a role for D-Asp as a potential vulnerability factor in SCZ.…”

Section: Discussionmentioning

confidence: 63%

“…23 Because D-Asp concentration is regulated by DDO, 26,35,36 we measured the levels of DDO mRNA in the PFC of SCZ patients by qRT-PCR. Statistical analysis revealed a significant increase in DDO mRNA of patients D-aspartate affects schizophrenia-related symptoms F Errico et al with SCZ, compared with healthy subjects (P = 0.0020, analysis of covariance with covariance for postmortem delay, Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…Consistently, we recently described a substantial reduction of D-Asp and of its N-methyl derivative, NMDA, in postmortem PFC of SCZ patients, compared with healthy individuals. 23 In the present study, we investigated the molecular determinants of the altered D-Asp brain content previously described in SCZ patients. Moreover, in an effort to backtranslate the human findings, we used Ddo − / − mice to demonstrate that increased DAsp levels, since perinatal phase, can attenuate PCP-induced SCZlike behaviors and their underlying circuital effectors, and affect the development of cortico-hippocampal connectivity networks, reported to be involved in SCZ.…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

Squillace

Errico

D’Argenio

et al. 2015

European Psychiatry

View full text Add to dashboard Cite

Increasing evidence points to a role for dysfunctional glutamate N-methyl-D-aspartate receptor (NMDAR) neurotransmission in schizophrenia. D-aspartate is an atypical amino acid that activates NMDARs through binding to the glutamate site on GluN2 subunits. D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-aspartate oxidase (DDO). The agonistic activity exerted by D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for some of the NMDAR-related alterations observed in schizophrenia. Consistently, substantial reductions of D-aspartate and NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the D-aspartate imbalance previously described. To investigate whether altered D-aspartate levels can modulate schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist, phencyclidine, in Ddo knockout mice (Ddo −/ − ), an animal model characterized by tonically increased D-aspartate levels since perinatal life. We show that Ddo − / − mice display a significant reduction in motor hyperactivity and prepulse inhibition deficit induced by phencyclidine, compared with controls. Furthermore, we reveal that increased levels of D-aspartate in Ddo − / − animals can significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia. Collectively, the present results suggest that altered D-aspartate levels can influence neurodevelopmental brain processes relevant to schizophrenia.

show abstract

Decreased levels of d-aspartate and NMDA in the prefrontal cortex and striatum of patients with schizophrenia

Cited by 86 publications

References 58 publications

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

Contact Info

Product

Resources

About