Samantha Rossano1,2, Takuya Toyonaga3, Eric Berg4, Isabella Lorence3, Krista Fowles3, Nabeel Nabulsi3, Jim Ropchan3, Songye Li3, Yunpeng Ye3, Zachary Felchner3, David Kukis5, Yiyun Huang3, Helene Benveniste6, Alice F Tarantal7, Stephanie Groman8,9, Richard E Carson3,10. 1. Department of Radiology and Biomedical Imaging, Yale PET Center, Yale School of Medicine, New Haven, CT, USA. samantha.rossano@yale.edu. 2. Department of Biomedical Engineering, Yale University, New Haven, CT, USA. samantha.rossano@yale.edu. 3. Department of Radiology and Biomedical Imaging, Yale PET Center, Yale School of Medicine, New Haven, CT, USA. 4. Department of Biomedical Engineering, University of California, Davis, CA, USA. 5. Center for Molecular and Genomic Imaging, University of California, Davis, CA, USA. 6. Department of Anesthesiology, Yale School of Medicine, Yale University, New Haven, CT, USA. 7. Departments of Pediatrics and Cell Biology and Human Anatomy, School of Medicine, and California National Primate Research Center, University of California, Davis, CA, USA. 8. Department of Psychiatry, Yale University, New Haven, CT, USA. 9. Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA. 10. Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
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 developing 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.
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 developing 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.