Density of metabotropic glutamate receptors 2 and 3 (mGluR2/3) in the dorsolateral prefrontal cortex does not differ with schizophrenia diagnosis but decreases with age

Frank, Elisabeth; Newell, Kelly A.; Huang, Xu‐Feng

doi:10.1016/j.schres.2011.01.008

Cited by 28 publications

(20 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings suggest that there are no pathological alterations of mGluR5 expression in the DLPFC, and therefore mGluR5 expression does not contribute to these cognitive deficits. These findings may extend to other mGluRs, such as mGluR2/3, which have been previously reported as unchanged in the same cohort (Frank et al, 2011).…”

Section: Mglur5 Binding Density and Protein Levels Are Unaltered In Tsupporting

confidence: 83%

Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment

Matosin

Frank

Deng

et al. 2013

Schizophrenia Research

Self Cite

View full text Add to dashboard Cite

Metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [3H]MPEP binding to mGluR5 and mGluR5 protein density in the post-mortem dorsolateral prefrontal cortex (DLPFC; BA46) of 37 schizophrenia and 37 matched control subjects. Subsequently, we measured [3H]MPEP binding in rat brains following typical (haloperidol) or atypical (olanzapine) antipsychotic treatment (n = 6/group). Subjects with schizophrenia showed no significant alteration in mGluR5 binding density or mGluR5 protein levels. Furthermore, mGluR5 binding in the rat cortex, thalamus, hippocampus and striatum was unaltered by short-, medium-and long-term antipsychotic treatment. Our data suggests that there are no alterations in mGluR5 in schizophrenia subjects. The lack of alteration in mGluR5 binding and protein in schizophrenia is advantageous because its ability to modulate the NMDAR is potentially unhindered, thereby supporting the development of novel antipsychotic agents that work through the mGluR5/NMDAR complex. ', Schizophrenia Research, vol. 146,[1][2][3] AbstractMetabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [ 3 H]MPEP binding to mGluR5 and mGluR5 protein density in post-mortem dorsolateral prefrontal cortex (DLPFC; BA46) of 37 schizophrenia subjects (including 7 schizoaffective) and 37 matched controls. Subsequently, we measured [ 3 H]MPEP binding in rat brains following typical (haloperidol) or atypical (olanzapine) antipsychotic treatment (n=6/group). Subjects with schizophrenia (n=30) showed no significant alteration in mGluR5 binding density or mGluR5 protein levels. However subjects with schizoaffective disorder (n=7) displayed a trend towards reduced mGluR5 binding (20%) compared to schizophrenia subjects (p=0.079), suggesting different underlying biochemistry of the disorder. In schizoaffective subjects of depressive subtype (n=4), mGluR5 binding was reduced by 39% compared to controls (p=0.022). Furthermore, mGluR5 binding in the rat cortex, thalamus, hippocampus and striatum was unaltered by short-, medium-and long-term antipsychotic treatment. Our data suggests that there are diagnostic specific alte...

show abstract

Section: Mglur5 Binding Density and Protein Levels Are Unaltered In Tsupporting

confidence: 83%

Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment

Matosin

Frank

Deng

et al. 2013

Schizophrenia Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…While mGluR binding, to our knowledge, has not previously been measured in individuals with BD, studies in the prefrontal cortex, thalamus and striatum of individuals with schizophrenia have likewise reported no change in mGluR2/3 19,[27][28][29][30] or mGluR5 11,21 (binding, protein or mRNA). Our findings highlight that in the ACC there are no distinct differences between the overlapping diagnoses of MDNP, MDP, schizophrenia and BD with regards to binding to mGluR2/3 and mGluR5.…”

Section: Mglur2/3 and Mglur5 Binding Does Not Differ In Bd And Schizomentioning

confidence: 69%

“…Previous postmortem studies have reported no association between antipsychotic dose and mGluR2/3 19,27,28 or mGluR5, 21 specifically in patients with schizophrenia. Animal studies have reported no effect of antipsychotics on mGluR2/3 34 or mGluR5 binding.…”

Section: Current and Novel Pharmacotherapy Implicationsmentioning

confidence: 77%

See 1 more Smart Citation

Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics

Matosin

Fernandez

Frank

et al. 2014

jpn

Self Cite

View full text Add to dashboard Cite

“…The expression of mGluR2/3 in cortical regions appears to vary between populations of patients, with reduced (Corti et al, 2007;Ghose et al, 2009;González-Maeso et al, 2008;Gupta et al, 2005) and unchanged levels being reported (Frank et al, 2011;Matosin et al, 2014). In accordance, increasing the activity of mGluR2/3 receptors might therefore be a viable treatment strategy.…”

Section: The Mglur2/3 Agonist Ly379268 Restores Nmda-r and Gabaa-r Exmentioning

confidence: 97%

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

et al. 2016

Self Cite

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

Density of metabotropic glutamate receptors 2 and 3 (mGluR2/3) in the dorsolateral prefrontal cortex does not differ with schizophrenia diagnosis but decreases with age

Cited by 28 publications

References 23 publications

Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment

Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment

Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics

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

Contact Info

Product

Resources

About