Synaptogenesis during brain development: A 11C-UCB-J PET Study in adolescent rats

77 Introduction: The PET radioligand 11C‑UCB‑J binds to the synaptic vesicle glycoprotein 2 (SV2A) to enable in vivo quantification of synaptic density1,2. In previous work, we found that SV2A binding is lower in a transgenic Alzheimer’s disease (AD) mouse model, reflecting disease-related synaptic loss3. This study also showed significant SV2A increases following treatment with a potential AD therapeutic drug3. Thus, SV2A could be a biomarker for synaptogenesis as well as synaptic loss. In fact, we have reported that 11C-UCB-J PET in the pregnant non-human primate demonstrated progressive increases in the fetal brain that can be interpreted as synaptogenesis during brain development. We, therefore, evaluated 11C‑UCB‑J PET imaging in rats to provide insights into synaptogenesis dynamics. Materials and Methods: Four rats were included in a longitudinal study and 24 rats were included in a cross-sectional study. The subjects in the longitudinal study were pair-housed reared in standard experimental environment. They underwent two 11C‑UCB‑J scans at postnatal day (PND) 30 and PND 60. The subjects for the cross-sectional study were separated into 3 groups at weaning; 1) single-housed in a standard environment, 2) single-housed in an enriched environment, 3) pair-housed in an enriched environment. The enriched environment included toys or tunnels in the cages. Half of these animals were scanned at PND 30 and the others at PND 60 (n=4 per group, in total n=12, at each time point). All animals in the cross-sectional study were euthanized after the PET scans to collect brain tissues for ex vivo validation. Rats were scanned with a Focus 220 scanner (Siemens, Knoxville, TN). Two to three rats were scanned simultaneously under isoflurane anesthesia. A transmission scan was acquired for attenuation correction. Rats received a bolus injection of 11C-UCB-J (12.3±4.8 MBq) by tail vein or IM injection and PET data were acquired for 60 min in list-mode. PET images were reconstructed with the 3D-OSEM/MAP algorithm, including corrections for attenuation and scatter, and then registered to the Waxholm Space (WHS) rat brain template with a 9 degree-of-freedom linear registration using FMRIB9s Linear Image Registration Tool in FSL. Radioactivity values were extracted from neocortex, striatum, thalamus, and cerebellum regions of interest using the WHS atlas. The outcome measure was the distribution volume ratio (DVR), the ratio between target and reference region, estimated by the simplified reference tissue model (SRTM) using brain stem as the reference region. Results: For the longitudinal study, the DVR of hippocampus, thalamus, and striatum showed significant increases from PND 30 to 60 (p Conclusions: 11C‑UCB‑J in adolescent rats demonstrated increased DVR at PND 60 and there was regional variation in this pattern, suggesting that during brain development from PND 30 to 60 in rats, synaptogenesis in hippocampus, striatum, and thalamus is greater than that in neocortex and cerebellum. Previous literature based on post-mortem analysis showed that different rearing environments affect synaptic development, however, our in vivo results could not replicate those findings to date. References: 1. Nabulsi et al., JNM, 2016. 2. Finnema et al., Sci Transl Med, 2016. 3. Toyonaga et al., JNM 2019.