Synaptic changes in psychiatric and neurological disorders: state-of-the art of in vivo imaging

Abstract

Synapses are implicated in many neuropsychiatric illnesses. Here, we provide an overview of in vivo techniques to index synaptic markers in patients. Several positron emission tomography (PET) tracers for synaptic vesicle glycoprotein 2 A (SV2A) show good reliability and selectivity. We review over 50 clinical studies including over 1700 participants, and compare findings in healthy ageing and across disorders, including addiction, schizophrenia, depression, posttraumatic stress disorder, and neurodegenerative disorders, including tauopathies, Huntington's disease and α-synucleinopathies. These show lower SV2A measures in cortical brain regions across most of these disorders relative to healthy volunteers, with the most well-replicated findings in tauopathies, whilst changes in Huntington's chorea, Parkinson's disease, corticobasal degeneration and progressive supranuclear palsy are predominantly subcortical. SV2A PET measures are correlated with functional connectivity across brain networks, and a number of other measures of brain function, including glucose metabolism. However, the majority of studies found no relationship between grey matter volume measured with magnetic resonance imaging and SV2A PET measures. Cognitive dysfunction, in domains including working memory and executive function, show replicated inverse relationships with SV2A measures across diagnoses, and initial findings also suggest transdiagnostic relationships with mood and anxiety symptoms. This suggests that synaptic abnormalities could be a common pathophysiological substrate underlying cognitive and, potentially, affective symptoms. We consider limitations of evidence and future directions; highlighting the need to develop postsynaptic imaging markers and for longitudinal studies to test causal mechanisms.

Fig. 1. Structure of a typical synapse and synaptic vesicle.

a Overview of the synapse, showing the presynaptic terminal with vesicles containing neurotransmitter, synaptic gap, and the postsynaptic density with neurotransmitter binding to receptors. Action potentials (arrow) trigger vesicular fusion with the presynaptic membrane to release neurotransmitter (b), which then diffuses across the synaptic gap to bind to receptors in the post-synaptic density. b Representation of a vesicle primed for fusion with the presynaptic membrane, showing key vesicle proteins. SNARE soluble N-ethylamide-sensitive factor attachment protein receptor complex.

Fig. 2. Colocalisation of SV2A and synaptophysin in the baboon brain.

a High-power confocal microscopy of 4’,6-diamidino-2-phenylindole (DAPI), synaptophysin (SYN), and synaptic vesicle glycoprotein 2A (SV2A) in the grey matter of the baboon brain. Labelling for SYN and SV2A is evident as punctate staining in the neuropil, particularly surrounding neuronal cell bodies and proximal dendrites (yellow arrow), but absent in neuronal cell bodies (white arrows). Nuclei are indicated by the DAPI stain in blue. b Correlation between in vitro SV2A and in vitro SYN density in grey matter regions determined using Western blot analyses. Data are nine brain regions. Figure and legend reproduced from Finnema et al. with permission (2016) [47]. GM grey matter, OD optical density.