Abstract
Purpose
Exploring synaptic density changes during brain growth is crucial to understanding brain development. Previous studies in nonhuman primates report a rapid increase in synapse number between the late gestational period and the early neonatal period, such that synaptic density approaches adult levels by birth. Prenatal synaptic development may have an enduring impact on postnatal brain development, but precisely how synaptic density changes in utero are unknown because current methods to quantify synaptic density are invasive and require post-mortem brain tissue.
Methods
We used synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) radioligands [11C]UCB-J and [18F]Syn-VesT-1 to conduct the first assessment of synaptic density in the develo** fetal brain in gravid rhesus monkeys. Eight pregnant monkeys were scanned twice during the third trimester at two imaging sites. Fetal post-mortem samples were collected near term in a subset of subjects to quantify SV2A density by Western blot.
Results
Image-derived fetal brain SV2A measures increased during the third trimester. SV2A concentrations were greater in subcortical regions than in cortical regions at both gestational ages. Near term, SV2A density was higher in primary motor and visual areas than respective associative regions. Post-mortem quantification of SV2A density was significantly correlated with regional SV2A PET measures.
Conclusion
While further study is needed to determine the exact relationship of SV2A and synaptic density, the imaging paradigm developed in the current study allows for the effective in vivo study of SV2A development in the fetal brain.
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Availability of data and material
The raw data and datasets used and/or analyzed in the current study will be made available upon reasonable request to the corresponding and participating authors as deemed appropriate, and in line with the data sharing policy.
Code of Availability
The code used in the current study will be made available upon reasonable request to the corresponding and participating authors as deemed appropriate, and in line with the data sharing policy.
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Acknowledgements
The authors acknowledge the nonhuman primate team at the Yale PET Center, including Daniel Holden, Cynthia Santaniello, Courtney Chabina, Kristin Koehl-Carabetta, and Amanda Harsche, for their assistance in completing the PET studies. The authors also acknowledge Dr. Alvaro Duque and the Rakic Breeding Colony for their assistance with NHP breeding at Yale and the staff at the California National Primate Research Center.
Funding
These studies were supported by National Institutes of Health (NIH) grants (no. MH120615 [SG], and no. U42-OD027094 [AT]), and the California National Primate Research Center base operating grant (no. OD011107). In vivo imaging was performed with instrumentation funded by the NIH (S10 grants RR029245, OD016261, and RR025063), and supported through the Primate Center Multimodal Imaging Core.
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SR collected and analyzed PET data, completed Western blotting and analysis, and prepared manuscript; TT supervised Western blotting and analysis, and manuscript preparation; EB collected and reconstructed PET data; IL analyzed PET data; KF performed PET imaging and data collection; NN, JR, SL, YY, ZF, and HH developed, synthesized, and QC of PET tracers; DK synthesized PET tracers; HB contributed to study design; AFT identified and assigned animals, performed all monitoring and imaging including ultrasound and PET/CT, data collection, performed all fetal tissue collections, contributed to study design, and manuscript preparation; SG analyzed PET data, contributed to study design, and manuscript preparation; REC contributed to study design, performed PET experiments, data analysis, and manuscript preparation.
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All procedures were carried out in strict accordance to the guidelines set forth in the Animal Welfare Act and the Guide for the Care and Use of Laboratory animals. All animal procedures were approved prior to implementation by Yale University’s Institutional Animal Care and Use Committee (IACUC) and by the IACUC at the University of California, Davis.
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Rossano, S., Toyonaga, T., Berg, E. et al. Imaging the fetal nonhuman primate brain with SV2A positron emission tomography (PET). Eur J Nucl Med Mol Imaging 49, 3679–3691 (2022). https://doi.org/10.1007/s00259-022-05825-6
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DOI: https://doi.org/10.1007/s00259-022-05825-6