Lower synaptic density is associated with depression severity and network alterations

Abstract

Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand [ 11 C]UCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls ( n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.

Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging

“…Third, medication effects cannot be ruled out as contributing to the current results, although brain penetrative medications were not administered for an average of 13 hours before PET measurements, and medications affecting SV2A were exclusionary criteria. Fourth, although we interpret SV2A differences as evidence of synaptic decreases, as noted recently, other interpretations are possible (eg, synaptic vesicle dysfunction and/or cycling). Preclinical work has shown, however, that synaptic vesicle pools are stable within synapses .…”

“…53 Last, it should be noted that other studies have used similar methodology with SV2A imaging at our center and also found disease-specific differences in SV2A in epilepsy, Alzheimer disease, and major depressive disorder. 12,29,35 Thus, emerging regional patterns in these diseases foster interest in the utility of SV2A as a wide-ranging neuropsychiatric biomarker for diagnosis, disease progression, and possibly treatment monitoring.…”

“…First, a nonlinear transformation grid was estimated between the AAL template and each subject's magnetic resonance (MR) image, using BioImage Suite software (v2.5; http://www.bioimagesuite.com). This nonlinear coregistration algorithm is a method first described in 2001 and subsequently used in multiple studies . Then, the subject's summed PET image (0–10 minutes postinjection) was coregistered to their MR image using a 6‐parameter rigid (linear) registration estimated with a mutual information algorithm (FMRIB's Linear Image Registration Tool, FMRIB Software Library).…”

“…This nonlinear coregistration algorithm is a March 2020 331 method first described in 2001 30 and subsequently used in multiple studies. 29,[31][32][33][34][35] Then, the subject's summed PET image (0-10 minutes postinjection) was coregistered to their MR image using a 6-parameter rigid (linear) registration estimated with a mutual information algorithm (FMRIB's Linear Image Registration Tool, FMRIB Software Library). Please see Figure 1 for a diagram of image registration processing.…”

Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis

“…Recent evidence from human brain imaging studies suggests that major depressive disorder is associated with reduced synaptic connections, which are likely linked to the observed differences in network functional connectivity 72 . The long-standing theory for how stressful experience alters mPFC dendritic spines and synapses is shaped as an inverse parabolic function.…”