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AMPA RECEPTOR BINDING POTENTIAL IS REDUCED IN THE ANTERIOR CINGULATE CORTEX OF FEMALE PATIENTS WITH PTSD

Nicholas Murphy — Alan Prossin2, Julia Engelhardt1, Krisha Shah1, Ioana Murgulet1, Richard Le3, Meixiang Yu3, Andreas Weyland4, Takuya Takahashi5, Sanjay J. Mathew1 1Texas A and M University, Naresh K. Vashisht College of Medicine, 2University of Texas Health Science Center at Houston, 3Houston Methodist Research Institute, 4Baylor College of Medicine, 5Yokohama City University of Graduate School of Medicine Nicholas Murphy, Texas A and M University, Naresh K. Vashisht College of Medicine

2026 ASCP Annual Meeting

Post-traumatic stress disorder (PTSD) is a common, serious, and disabling condition with few effective treatments. Improved understanding of PTSD brain mechanisms is critical to the development of novel therapeutics. Glutamatergic modulation in PTSD is associated with the relief of behavioral symptoms. However, current approaches that focus on the NMDA receptor may not be sufficient targets for long term maintenance of improvements. Targeting AMPA receptors may provide the dynamic modulation of longterm potential necessary to sustain clinical benefits. Pre-clinical work presents strong support for the role of AMPA receptor (AMPAR) mediated impairments to synaptic plasticity in the pathophysiology of PTSD. Accordingly, the recent discovery of a selective positron emission tomography (PET) radiotracer ([11C]K-2) for AMPA glutamate receptors has broad potential applications for PTSD and CNS disorders marked by imbalances in excitatory/inhibitory synapses. [C11]K2 is a novel PET radioligand which targets an AMPA glutamate receptor allosteric modulatory site, a target of critical importance in PTSD due to their role in E/I synaptic transmission. We present findings from a cross-sectional study of [C11]K2 AMPA receptor binding potential (AMPABPND) in PTSD. Participants were N=10 PTSD (31.6 years ± 8.19) and N=10 trauma-naive controls (25.6 years ± 3.78). We restricted recruitment to female patients to limit biological heterogeneity and the influence of menstrual hormones. Patients met DSM-5 criteria for chronic PTSD and had a CAPS-5 score (past month) > = 35. PET imaging of the brain used a Siemens Biograph Vision PET/CT Scanner. White matter served as the reference region. Statistical modeling used one-way ANCOVA with one factor (Diagnosis) and one behavioral covariate (CAPS-5). Voxel-wise, whole-brain statistical analyses were completed within Statistical Parametric Mapping software. Significance was set to puncorr < 0.01 for a-priori hypothesized brain regions (PFC, OFC, amygdala, hippocampus) and puncorr < 0.005 for other regions. Wholebrain voxelwise analyses revealed significantly lower AMPAR binding potential in PTSD relative to controls within the bilateral middle cingulate cortex. Left MCC: T₁₇ = 2.93, p < 0.005; Right MCC: T₁₇ = 2.95, p < 0.004 . Within the PTSD group, ACC AMPAR BPND was strongly negatively correlated with symptom severity, such that lower receptor availability predicted higher CAPS-5 scores: T₈ = 5.02, r = –0.87, p < 0.0005 . No significant group differences or correlations emerged in other a priori ROIs. This pilot study provides the first PET-based evidence that cingulate AMPA receptor availability is reduced in women with chronic PTSD, aligning with preclinical models implicating disrupted excitatory synaptic plasticity in fearlearning circuits. The robust association between ACC AMPAR BPND and symptom severity suggests that AMPAR-mediated signaling may be a mechanistic contributor to core PTSD pathology and a potential biomarker for treatment response. Preliminary evidence of reduced ACC AMPABPND in PTSD helps to advance translation of animal models of fear response learning. Larger, mixed-sex, and longitudinal studies are needed to establish causal relationships, evaluate treatment sensitivity (e.g., ketamine, AMPAR PAMs), and determine whether AMPAR PET imaging can guide patient-specific therapeutic strategies.

Learning Objective 1: Understand the need for glutamate based clinical targets related to PTSD pathophysiology

Learning Objective 2: Understand how PET imaging can be used to study the molecular mechanisms of clinical symptoms

References

: Miyazaki T, Nakajima W, Hatano M, Shibata Y, Kuroki Y, Arisawa T, Serizawa A, Sano A, Kogami S, Yamanoue T, Kimura K, Hirata Y, Takada Y, Ishiwata Y, Sonoda M, Tokunaga M, Seki C, Nagai Y, Minamimoto T, Kawamura K, Zhang MR, Ikegaya N, Iwasaki M, Kunii N, Kimura Y, Yamashita F, Taguri M, Tani H, Nagai N, Koizumi T, Nakajima S, Mimura M, Yuzaki M, Kato H, Higuchi M, Uchida H, Takahashi T. Visualization of AMPA receptors in living human brain with positron emission tomography. Nat Med. 2020 Feb;26(2):281-288. doi: 10.1038/s41591-019-0723-9. Epub 2020 Jan 20.