Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study

Abstract

Objective: Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects.

Method: Images of mGluR5 receptor binding were acquired using PET with [(11)C]ABP688, which binds to an allosteric site with high specificity, in 11 unmedicated individuals with major depression and 11 matched healthy comparison subjects. The amount of mGluR5 protein was investigated using Western blot in postmortem brain samples of 15 depressed individuals and 15 matched comparison subjects.

Results: The PET study revealed lower levels of regional mGluR5 binding in the prefrontal cortex, the cingulate cortex, the insula, the thalamus, and the hippocampus in the depression group relative to the comparison group. Severity of depression was negatively correlated with mGluR5 binding in the hippocampus. The postmortem study showed lower levels of mGluR5 protein expression in the prefrontal cortex (Brodmann's area 10) in the depression group relative to the comparison group, while prefrontal mGluR1 protein expression did not differ between groups.

Conclusions: The lower levels of mGluR5 binding observed in the depression group are consonant with the lower levels of protein expression in brain tissue in the postmortem depression group. Thus, both studies suggest that basal or compensatory changes in excitatory neurotransmission play roles in the pathophysiology of major depression.

Conflict of interest statement

Conflict of Interest

Alexandra Deschwanden, Beata Karolewicz, Anteneh M. Feyissa, Valerie Treyer, Simon M. Ametamey, Anass Johayem, Craig A. Stockmeier, Alfred Buck and Gregor Hasler do not have a conflict of interest regarding the content of this article. Yves Auberson and Judit Sovago work for Novartis Pharma AG (Basel, Switzerland) that is developing and testing drugs targeting the mGlu5 receptor.

Figures

Figure 1

Statistical parametric map illustrating brain regions where the metabotrophic glutamate receptor subtype 5 (mGluR5) density was decreased in subjects with major depressive disorder versus healthy controls. The voxel T values correspond to p < 0.01 for the contrast of DVR between groups and are displayed on axial (A, z: −2), sagittal (B, x: −52) and coronal (C, y: −33; D, y: 51) sections of a spatially normalized and averaged MRI from the study sample. The regions are labelled with the following letters ordered by decreasing t values (Table 1): (a) right mesencephalon / thalamus, (b) right middle / inferior temporal gyrus, (c) left inferior parietal lobe, (d) left middle / inferior temporal gyrus, (e) right precentral gyrus, (f) right anterior insula / inferior prefrontal gyrus, (g) left medial orbital cortex (Brodmann's area 11), (h) left frontal polar cortex (Brodmann's area 10), (i) right lateral prefrontal cortex (Brodmann's area 46). The color bar indicates the voxel T value. Abbreviations: A, anterior; P, posterior; S, superior; I, inferior; L, left; R, right.

Figure 2

Image sections (A, C) obtained with Statistical Parametric Mapping software (SPM99; Wellcome Department of Imaging Neuroscience, London, England) and graphs (B, D, E) illustrating correlations between mGluR5 DVR and symptom severity as assessed by the Beck Depression Inventory (BDI; A, B) and the Beck Anxiety Inventory (BAI; C, D, E) in the depressed sample (N=11). In A and C, correlation maps are displayed on axial sections of a spatially normalized and averaged MRI from the study sample; in A (z=7), voxel t values correspond to pT value; a, right hippocampal formation; b, left thalamus; c, right thalamus. In B, D and E, symptoms scores are plotted against mGluR5 DVR. Correlation coefficients and p values in the right hippocampal formation (B), the right thalamus (D) and the left thalamus (E) were determined using Pearson correlation. The regression lines were determined using linear regression. Abbreviations: A, anterior; P, posterior; L, left; R, right.

Figure 3

mGluR5 immunoreactivity in the right prefrontal cortex (Brodmann's area 10) from six male subjects used in the analysis. The bottom panel shows immunoreactive actin detected on the same blot. Each well was loaded with 15 µg of total protein. HC, healthy control; MDD, major depressive disorder; M, male.

Figure 4

Column scatter graphs displaying mGluR5 protein levels found in the postmortem study (A), and mGluR5 binding found in the PET study (B). Both measures were derived from the identical location within the right frontal polar cortex (Brodmann's area 10; see method section). In A, the mGluR5 protein levels were normalized to actin. In B, mGluR5 DVR. Unpaired t-tests were used to compare subjects with major depressive disorder (MDD) with healthy controls (HC). In A, group means (SDs) of the mGluR5/actin ratio were 1.25 (0.52) in HC and 0.85 (0.30) in major depression. In B, group means (SDs) mGluR5 DVR were 1.37 (0.14) in HC and 1.25 (0.08) in major depression.