Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression

Abstract

Clinical, postmortem and preclinical research strongly implicates dysregulation of glutamatergic neurotransmission in major depressive disorder (MDD). Recently, metabotropic glutamate receptors (mGluRs) have been proposed as attractive targets for discovery of novel therapeutic approaches against depression. The aim of this study was to examine mGluR2/3 protein levels in the prefrontal cortex (PFC) from depressed subjects. In addition, to test whether antidepressants influence mGluR2/3 expression we also studied levels of mGluR2/3 in fluoxetine treated monkeys. Postmortem human prefrontal samples containing Brodmann’s area 10 (BA 10) were obtained from 11 depressed and 11 psychiatrically healthy controls. Male rhesus monkeys were treated chronically with fluoxetine (dose escalated to 3mg/kg, p.o; n=7) or placebo (n=6) for 39 weeks. The mGluR2/3 immunoreactivity was investigated using Western blot method. There was a robust (+67%) increase in the expression of the mGlu2/3 protein in the PFC of depressed subjects relative to healthy controls. The expression of mGlu2/3 was unchanged in the PFC of monkeys treated with fluoxetine. Our findings provide the first evidence that mGluR2/3 is elevated in the PFC in MDD. This observation is consistent with reports showing that mGluR2/3 antagonists exhibit antidepressant-like activity in animal models and demonstrates that these receptors are promising targets for the discovery of novel antidepressants.

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

“…9 We found no other studies that have investigated mGluRs in the ACC in individuals with depression. In other brain regions of depressed patients, an increase in mGluR2/3 24 and reduction of mGluR5 protein in the prefrontal cortex (BA10) have been reported, together with reduced (in vivo) prefrontal cortical mGluR5 binding 25 and increased mGluR5 gene expression in the locus coeruleus. 26 Although it is difficult to draw conclusions from only a small number of studies, the inconsistencies between these findings highlight the inherent regional differences in mGluRs in the pathophysiology of MD as well as the importance of considering psychiatric subclass.…”

Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder

“…15,47,48 Expression data from animal models of depression suggest that mGluR2/3 mRNA expression is reduced in the hippocampus. 49,50 Increased levels of the mGluR2/3 proteins also have been observed in the pre-frontal cortex of patients with major depressive disorder, 3 whereas both elevated 51 and reduced expression 52,53 levels of mGluR2/3 in the frontal cortex of patients with schizophrenia have been observed. Several mGluR2/3 agonists and antagonists have been established.…”

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of 11C-JNJ-42491293, A Novel Radioligand for mGluR2

“…In particular, mGluR2 is primarily expressed presynaptically where it reduces glutamate release and protects neurons from excitotoxicity, modulates dopaminergic and adrenergic neurotransmission, and participates in synaptic plasticity. As such, mGluR2 has been implicated in the pathogenesis of several neurologic and psychiatric disorders including schizophrenia (2), addiction (3), anxiety (4), major depression (5), and neurodegeneration (6,7). The cerebral distribution of mGluR2 messenger RNA and protein has been described in rodents (8,9) and humans (10,11), with expression throughout the cortex, striatum, thalamus, and cerebellum.…”

“…Drugs and imaging ligands targeting allosteric binding sites on mGluRs have been more tractable, and negative allosteric modulator PET ligands have been developed for mGluR1 (17)(18)(19) and mGluR5 (20). A radioligand that enables selective quantitative assessment of mGluR2 would be a major step forward in understanding the role of this receptor in the neurobiology of multiple brain disorders and a valuable tool for testing target engagement and dose occupancy of clinical drug leads with affinity for the same receptor site (5,21).…”