Uncovering the link between synaptic density and mental illness through in vivo imaging.

The in vivo study of synaptic density (the indirect estimated sum of presynaptic active zones and postsynaptic densities in brain tissue) through positron emission tomography (PET) is a rapidly growing field of research that has the potential to revolutionize our understanding of mental illness and of neurodevelopmental conditions. The idea that the brain’s synaptic wiring, neural function and behaviour are closely linked is not a new one, but advances in neuroimaging techniques have only recently made it possible to collect direct empirical data linking the status of brain synapses (synaptic density) with neural function, behaviour and disease in living humans. Forty-five years ago, Irwin Feinberg suggested that excessive synaptic pruning during adolescence could lead to severe mental illness. Unequivocal evidence to support this theory in living humans is still lacking. The overall objective of this editorial is to present our stance on the value of measuring synaptic density in vivo using PET to better understand the development of mental illness. We argue that this novel approach might be more translationally and conceptually useful than related techniques using MRI because it is likely more proximal to function. As such, it could generate an unprecedented level of comprehension on synaptic organ ization and pruning and its role in the development of mental illness. We first provide an overview of the keystone neuroscience concepts of synaptic communication and of synaptic pruning; we discuss the popular, though still unproven, theory that abnormal (excessive) synaptic pruning during brain development potentially leads to mental illness. We then provide our perspective on the utility of PET imaging of synaptic density and consider pitfalls and hurdles ahead in translating findings in a clinically meaningful way.