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. 2022 Aug 4:6:24705470221105804.
doi: 10.1177/24705470221105804. eCollection 2022 Jan-Dec.

Differential Role of mGluR5 in Cognitive Processes in Posttraumatic Stress Disorder and Major Depression

Irina Esterlis  1   2   3 , Sarah DeBonee  1 , Ryan Cool  1 , Sophie Holmes  1   2   3 , Stephen R Baldassari  4   5 , Paul Maruff  6 , Robert H Pietrzak  1   3 , Margaret T Davis  1   2   3
Affiliations

Differential Role of mGluR5 in Cognitive Processes in Posttraumatic Stress Disorder and Major Depression

Irina Esterlis et al. Chronic Stress (Thousand Oaks). .

Abstract

Background: A robust literature supports the role of the metabotropic glutamate receptor type 5 (mGluR5) in cognitive functioning. mGluR5 is also implicated in the pathophysiology of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), which are characterized by cognitive alterations. However, the relationship between mGluR5 and cognition in MDD and PTSD has not yet been directly investigated. To address this gap, we examined the relationship between in vivo mGluR5 availability and cognition in PTSD, MDD, and matched healthy adults (HA).

Methods: Individuals with PTSD (N = 28) and MDD (N = 21), and HA (N = 28) were matched for age, gender, and smoking status. Participants completed 18F-FPEB positron emission tomography (PET) scan, psychiatric and cognitive assessments.

Results: Across models examining the relationship between mGluR5 availability and different domains of cognition across diagnostic groups, only the interaction of diagnosis*attention was significant (F 4,64 = 3.011, P = .024). Higher mGluR5 availability was associated with poorer attention in PTSD in 4 frontolimbic regions of interests (ROI's: OFC (r = -.441, P = .016), vmPFC (r = -.408, P = .028), dlPFC (r = -.421, P = .023), hippocampus (r = -.422, P = .025). By contrast, mGluR5 availability in the MDD group was positively related to Attention (ATTN) in the OFC (r = .590, P = .006), vmPFC (r = .653, P = .002), and dlPFC (r = .620, P = .004). Findings in the hippocampus for MDD followed the same pattern but did not survive correction for multiple comparisons (r = .480, P = .036). ATTN and mGluR5 availability were not significantly related in the HA group. Of note, in MANOVA analyses group*ATTN interaction results in the OFC did not survive multiple comparisons (P = .046). All other findings survived correction for multiple comparisons and remained significant when covarying for potential confounds (eg, depressed mood).

Conclusions: We observed a significant relationship between frontolimbic mGluR5 availability and performance on tests of attention in individuals with MDD and PTSD. This finding aligns with animal work showing dysregulation in mGluR5 in cognitive functioning, and differed as a function of diagnosis. Results suggest interventions targeting mGluR5 may help bolster cognitive difficulties, highlighting the importance of employing different mGluR5 directed treatment strategies in MDD and PTSD.

Keywords: MDD; PET; PTSD; attention; cognition; mGluR5.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Maruff is a full-time employee of Cogstate Ltd He reports no other potential conflicts of interest. All other authors report no conflicts of interest, and have nothing further to disclose.

Figures

Figure 1.
Figure 1.
Panels illustrate differences between participants with posttraumatic stress disorder (PTSD, blue), major depressive disorder (MDD, purple), and healthy adults (HA, gray) in in vivo mGluR5 availability. Data are displayed for four brain regions (Study ROIs used in primary analyses): orbitofrontal cortex (OFC; top left), ventromedial prefrontal cortex (vmPFC; bottom left), dorsolateral prefrontal cortex (dlPFC; top right), hippocampus (bottom right).
Figure 2.
Figure 2.
Panels illustrate group differences in cognitive domain score performance between participants with posttraumatic stress disorder (PTSD, blue), major depressive disorder (MDD, purple), and healthy adults (HA, gray). Individuals’ data points are illustrated in addition to mean and 95% confidence intervals for each group. Panel A displays results from a composite score derived from two tasks measuring attention and psychomotor speed: Identification (IDN) and Detection (DET) tasks. Panel B displays results from a composite score derived from two tasks measuring working memory: Once Card Learning (OCL), and One Back (ONB) tasks. Panel C displays the results of the Groton Maze Learning (GML) task, a measure of executive functioning. Panel D displays results from the International Shopping List test (ISLT), measuring verbal learning.
Figure 3.
Figure 3.
Panels illustrate the relationships between in vivo mGluR5 availability in four brain regions orbitofrontal cortex (OFC; A), ventromedial prefrontal cortex (vmPFC; B), dorsolateral prefrontal cortex (dlPFC; C), hippocampus (D) and attention/ psychomotor speed (ATTN) assessed using a composite of the Cogstate identification (IDN) and detection (DET) tasks. mGluR5 availability in the PTSD group (blue, top row) was significantly negatively related to ATTN in all ROIs: OFC (r = −.441, P = .016), vmPFC (r = −.408, P = .028), dlPFC(r = −.421, P = .023), and hippocampus (r = −.422, P = .025). By contrast, mGluR5 availability in the MDD group (purple, middle row) was significantly positively related to ATTN in the OFC (r = .590, P = .006), vmPFC (r = .653, P = .002), and dlPFC (r = .620, P = .004) Findings in the hippocampus for MDD followed the same pattern, but did not survive correction for multiple comparisons (r = .480, P = .036). ATTN and mGluR5 availability were not significantly related in the HA group (gray, bottom row). Of note, in MANOVA analyses group*ATTN interaction results in the OFC did not survive multiple comparisons (P = .046).
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