Lower synaptic density is associated with depression severity and network alterations

TLDR

Synaptic loss and functional connectivity deficits are hypothesized to underlie symptoms of major depressive disorder and post‑traumatic stress disorder, with synaptic vesicle glycoprotein 2A (SV2A) serving as a biomarker for synaptic density. The study employed PET imaging with the SV2A radioligand [11C]UCB‑J to quantify synaptic density in 26 unmedicated participants with MDD, PTSD, or both. Lower synaptic density, as measured by SV2A PET, correlated with greater depressive symptom severity, reduced connectivity, and differed from healthy controls, providing the first in vivo evidence that synaptic loss underlies depression symptoms and network dysfunction and suggesting that restoring synaptic connections may be a therapeutic target.

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 [11C]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.