Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

Holmes, Sophie; Girgenti, Matthew J.; Davis, Margaret T.; Pietrzak, Robert H.; DellaGioia, Nicole; Nabulsi, Nabeel; Matuskey, David; Southwick, Steven M.; Duman, Ronald S.; Carson, Richard E.; Krystal, John H.; Esterlis, Irina

doi:10.1073/pnas.1701749114

Cited by 107 publications

(90 citation statements)

References 79 publications

(83 reference statements)

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“…In addition, the glucocorticoid receptor chaperone FKBP5 was identified as an upregulated key driver in the dlPFC of females with PTSD. Regulation of FKBP5 has also been reported in small, preliminary postmortem PTSD studies in OFC 64 and the sgPFC 65 and FKBP5 variants have been extensively implicated in risk for developing PTSD 66,67 . These results indicate that FKBP5 and UBA7 act as hub genes with functional importance in PTSD molecular pathology, consistent with previous work implicating dysregulation of inflammatory and GC signaling as hallmarks of PTSD pathophysiology.…”

Section: Discussionmentioning

confidence: 85%

Transcriptomic Organization of Human Posttraumatic Stress Disorder

Girgenti

Wang

et al. 2020

Preprint

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Posttraumatic stress disorder (PTSD) affects approximately 8% of the general population, with higher rates in extreme stress groups, including combat veterans or victims of sexual assault. Despite extensive study of the neurobiological correlates of PTSD, little is known about its molecular substrates. Here differential gene expression and network analyses of 4 prefrontal cortex (PFC) postmortem subregions of male and female PTSD subjects demonstrates extensive remodeling of the transcriptomic landscape. The data revealed a highly connected down-regulated set of interneuron transcripts in the most significant gene network associated with PTSD and integration of this data with genotype data from the largest PTSD GWAS identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked sexual dimorphism in the transcriptomic signatures that could contribute to the higher rates of PTSD in women. Comparison with a matched major depressive disorder (MDD) cohort revealed significant divergence between the molecular profiles of subjects with PTSD and depression despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the PFC that contribute to the pathophysiology of PTSD in humans.

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Section: Discussionmentioning

confidence: 85%

Transcriptomic Organization of Human Posttraumatic Stress Disorder

Girgenti

Wang

et al. 2020

Preprint

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“…For example, studies have reported changes in brain and blood glutamate concentrations in individuals with PTSD compared to control participants 18,19 . A positron emission tomography (PET) study showed that individuals with PTSD exhibit enhanced metabotropic glutamate receptor 5 (mGluR5) availability throughout the cortex 20,21 .…”

Section: The American Psychiatricmentioning

confidence: 99%

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

Tyler

Weinberg

Lovelock

et al. 2020

Preprint

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Persistent changes in brain stress and glutamatergic function are associated with post-traumatic stress disorder (PTSD). Rodent exposure to the predator odor trimethylthiazoline (TMT) is an innate stressor that produces lasting behavioral consequences relevant to PTSD. As such, the goal of the present study was to assess early (6 hours and 2 days) and late (4 weeks) changes to gene expression (RT-PCR) related to stress and excitatory function following TMT exposure in male, Long-Evans rats. During TMT exposure, rats engaged in stress reactive behaviors, including digging and immobility. Further, the TMT group displayed enhanced exploration and mobility in the TMT-paired context one week after exposure, suggesting a lasting contextual reactivity. Gene expression analyses revealed upregulated FKBP5 6 hours post-TMT in the hypothalamus and dorsal hippocampus. Two days after TMT, GRM3 was downregulated in the prelimbic cortex and dorsal hippocampus, but upregulated in the nucleus accumbens. This may reflect an early stress response (FKBP5) that resulted in later glutamatergic adaptation (GRM3).Finally, four weeks after TMT exposure, several differentially expressed genes known to mediate excitatory tripartite synaptic function were observed. Specifically in the prelimbic cortex (GRM5, DLG4 and SLC1A3 upregulated), infralimbic cortex (GRM2 downregulated, Homer1 upregulated), nucleus accumbens (GRM7 and SLC1A3 downregulated), dorsal hippocampus (FKBP5 and NR3C2 upregulated, SHANK3 downregulated) and ventral hippocampus (CNR1, GRM7, GRM5, SHANK3, and Homer1 downregulated). These data demonstrate that TMT exposure stress induces early and late stress and excitatory molecular adaptations, which may help us understand the persistent glutamatergic dysfunction observed in PTSD.

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“…In another recent report, we combined human postmortem gene expression profiling with neuroimaging to examine the possible disruption of glutamate cycling disruption in PTSD [63]. Live human photon emission topography (PET) was used to measure the difference in levels of metabotropic glutamate (mGlur5).…”

Section: Abnormal Gene Expression In the Pathophysiology Of Ptsdmentioning

confidence: 99%

“…All four SNPs interact with childhood abuse to predict PTSD lifetime severity including levels of hyperarousal and alterations in reactivity [69]. Further, decreased Fkpb5 transcript levels have been observed in peripheral blood and subgenual PFC of patients with PTSD [63]. …”

Section: Abnormal Gene Expression In the Pathophysiology Of Ptsdmentioning

confidence: 99%

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Girgenti

Hare

Ghosal

et al. 2017

Curr Psychiatry Rep

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Purpose of Review Posttraumatic stress disorder (PTSD) is characterized by hyperarousal and recurrent stressful memories after an emotionally traumatic event. Extensive research has been conducted to identify the neurobiological determinants that underlie the pathophysiology of PTSD. In this review, we examine evidence regarding the molecular and cellular pathophysiology of PTSD focusing on two primary brain regions: the vmPFC and the amygdala. Recent Findings This discussion includes a review of the molecular alterations related to PTSD, focusing mainly on changes to glucocorticoid receptor signaling. We also examine postmortem gene expression studies that have been conducted to date and the molecular changes that have been observed in peripheral blood studies of PTSD patients. Causal, mechanistic evidence is difficult to obtain in human studies, so we also review preclinical models of PTSD. Summary Integration of peripheral blood and postmortem studies with preclinical models of PTSD has begun to reveal the molecular changes occurring in patients with PTSD. These findings indicate that the pathophysiology of PTSD includes disruption of glucocorticoid signaling and inflammatory systems and occurs at the level of altered gene expression. We will assess the impact of these findings on the future of PTSD molecular research.

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Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

Cited by 107 publications

References 79 publications

Transcriptomic Organization of Human Posttraumatic Stress Disorder

Transcriptomic Organization of Human Posttraumatic Stress Disorder

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

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