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Spatial and temporal dynamics of HDACs class IIa following mild traumatic brain injury in adult rats

Molecular Psychiatry volume 27, pages 1683–1693 (2022)Cite this article

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Abstract

The fundamental role of epigenetic regulatory mechanisms involved in neuroplasticity and adaptive responses to traumatic brain injury (TBI) is gaining increased recognition. TBI-induced neurodegeneration is associated with several changes in the expression-activity of various epigenetic regulatory enzymes, including histone deacetylases (HDACs). In this study, PET/CT with 6-([18F]trifluoroacetamido)−1- hexanoicanilide ([18F]TFAHA) to image spatial and temporal dynamics of HDACs class IIa expression-activity in brains of adult rats subjected to a weight drop model of diffuse, non-penetrating, mild traumatic brain injury (mTBI). The mTBI model was validated by histopathological and immunohistochemical analyses of brain tissue sections for localization and magnitude of expression of heat-shock protein-70 kDa (HSP70), amyloid precursor protein (APP), cannabinoid receptor-2 (CB2), ionized calcium-binding adapter protein-1 (IBA1), histone deacetylase-4 and −5 (HDAC4 and HDAC5). In comparison to baseline, the expression-activities of HDAC4 and HDAC5 were downregulated in the hippocampus, nucleus accumbens, peri-3rd ventricular part of the thalamus, and substantia nigra at 1–3 days post mTBI, and remained low at 7–8 days post mTBI. Reduced levels of HDAC4 and HDAC5 expression observed in neurons of these brain regions post mTBI were associated with the reduced nuclear and neuropil levels of HDAC4 and HDAC5 with the shift to perinuclear localization of these enzymes. These results support the rationale for the development of therapeutic strategies to upregulate expression-activity of HDACs class IIa post-TBI. PET/CT (MRI) with [18F]TFAHA can facilitate the development and clinical translation of unique therapeutic approaches to upregulate the expression and activity of HDACs class IIa enzymes in the brain after TBI.

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Fig. 1: PET/CT images of the rat brain at 20–30 min post [18F]TFAHA administration obtained at baseline, 1–3 days, and 7–8 days post-TBI.
Fig. 2: Changes in [18F]TFAHA accumulation in different structures of the rat brain at baseline and different days post TBI in peri-3rd ventricular thalamic gray matter (PTG), n. accumbens, hippocampus, and substantia nigra.
Fig. 3: Expression of HDAC4 in the rat hippocampus at baseline, 1–3 days, and 7–8 days post-TBI, visualized by IHC.
Fig. 4: Expression of HDAC4 and HDAC5 in the paraventricular thalamic nucleus in the rat brain.
Fig. 5: Expression of HDAC5 in the rat hippocampus at baseline, 1–3 days, and 7-8 days post-TBI, visualized by IHC.
Fig. 6: The ratio of cytoplasmic vs nuclear localization/expression levels of HDAC4 and HDAC5 in different structures of the rat brain.

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Acknowledgements

These studies were supported in part by the grants: R01DA042057 (NIDA/NIH) to SP and JGG; and RX002900 (VA) to AC and JGG. The Microscopy, Imaging, and Cytometry Resources Core are supported, in part, by the Cancer Center Support Grant (P30 CA022453, NCI/NIH) to Karmanos Cancer Institute, Wayne State University, Detroit, MI; RP and WA received awards from the Levy-Logenbaugh Donor-Advised Fund.

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Authors and Affiliations

  1. Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, MI, 48201, USA

    Swatabdi R. Kamal, Shreya Potukutchi, John M. Cavanaugh & Juri G. Gelovani

  2. School of Medicine, Wayne State University, Detroit, MI, 48201, USA

    David J. Gelovani & Robin E. Bonomi

  3. Department of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, MI, 48201, USA

    Srinivasu Kallakuri & Shane A. Perrine

  4. Cyclotron-Radiochemistry Facility, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA

    Thomas Mangner

  5. Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA

    Thomas Mangner & Renata Pasqualini

  6. Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, 48201, USA

    Alana Conti

  7. Departments of Neurosurgery and Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Alana Conti

  8. Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

    Ren-Shyan Liu

  9. Department of Nuclear Medicine, Cheng-Hsin General Hospital, Taipei, 112, Taiwan

    Ren-Shyan Liu

  10. Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan

    Ren-Shyan Liu

  11. Rutgers Cancer Institute of New Jersey, Newark, NJ, 07103, USA

    Renata Pasqualini & Wadih Arap

  12. Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA

    Wadih Arap

  13. Department of Neurology, Harvard Medical School, Boston, MA, 02115, USA

    Richard L. Sidman

  14. Molecular Imaging Program, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA

    Juri G. Gelovani

  15. College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE

    Juri G. Gelovani

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  1. Swatabdi R. Kamal
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  2. Shreya Potukutchi
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Contributions

SRK, RP, WA, RLS, SAP, and JGG designed research; SRK, SP, DJG, RB, SK, and JGG performed research; RB, TM, and JGG contributed new reagents/analytic tools; SRK, SP, DJG, RP, JMC, WA, AC, RLS, SAP, and JGG, analyzed data; SRK, SK, RP, WA, RLS, SAP, and JGG, wrote the paper.

Corresponding author

Correspondence to Juri G. Gelovani.

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Competing interests

RB and JGG are inventors on issued patents and pending patent applications related to PET imaging of HDACs class IIa expression-activity and are entitled to royalties if licensing or commercialization occurs. Potential conflicts of interest are managed in accordance with established institutional conflict of interest policies of the Wayne State University (Detroit, MI). The other authors declare that no conflicts of interest exist.

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Kamal, S.R., Potukutchi, S., Gelovani, D.J. et al. Spatial and temporal dynamics of HDACs class IIa following mild traumatic brain injury in adult rats. Mol Psychiatry 27, 1683–1693 (2022). https://doi.org/10.1038/s41380-021-01369-7

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