Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression.

A review describes the development of PET radiotracers targeting the synaptic vesicle glycoprotein 2A (SV2A), which allows measurement of synaptic density in living brains. In depression, lower SV2A density is found in people with significant depressive symptoms. A ketamine challenge was used to examine synaptogenesis in vivo. The authors stress the value of combining clinical imaging with animal model studies, presenting preliminary findings from chronic stress models. Methodological challenges and future directions for SV2A imaging, possibly alongside other neural markers, are discussed.

Study at a glance

Abstract

The development of novel radiotracers for Positron Emission Tomography (PET) imaging agents targeting the synaptic vesicle glycoprotein 2 A (SV2A), an integral glycoprotein present in the membrane of all synaptic vesicles throughout the central nervous system, provides a method for the in vivo quantification of synaptic density. This is of particular interest in neuropsychiatric disorders given that synaptic alterations appear to underlie disease progression and symptom severity. In this review, we briefly describe the development of these SV2A tracers and the evaluation of quantification methods. Next, we discuss application of SV2A PET imaging to the study of depression, including a review of our findings demonstrating lower SV2A synaptic density in people with significant depressive symptoms and the use of a ketamine drug challenge to examine synaptogenesis in vivo. We then highlight the importance of performing translational PET imaging in animal models in conjunction with clinical imaging. We consider the ongoing challenges, possible solutions, and present preliminary findings from our lab demonstrating the translational benefit and potential of in vivo SV2A imaging in animal models of chronic stress. Finally, we discuss methodological improvements and future directions for SV2A imaging, potentially in conjunction with other neural markers.