Lower synaptic density is associated with depression severity and network alterations

Sophie E Holmes,Margaret T Davis,Irina Esterlis,Ronald S Duman,Gerard Sanacora,John H Krystal,Mika Naganawa,Gustavo A Angarita,Dustin Scheinost,Nicole Dellagioia,Robert H Pietrzak,Sjoerd J Finnema,Nabeel Nabulsi,Richard E Carson,David Matuskey

doi:10.1038/s41467-019-09562-7

Sophie E Holmes, Margaret T Davis + Show 13 more

Open Access

https://doi.org/10.1038/s41467-019-09562-7

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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.

Highlights

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)
There were no correlations between verbal learning, memory or visual attention tasks and functional connectivity measures. These exploratory findings did not survive correction for multiple comparisons. This is the first study to investigate radioligand binding to synaptic vesicle glycoprotein 2A (SV2A) in MDD and PTSD, and the first in vivo evidence of lower synaptic density in association with depressive symptoms in these disorders
Findings suggest that lower synaptic density contributes to the severity of depression in regions associated with affective processing, transdiagnostically

Summary

Introduction

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). SV2A density was 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. Persisting high levels of stress are thought to result in loss of synapses in circuits underlying affective and cognitive processes[1] These reductions are presumed to contribute to the symptoms of depression associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD)—highly comorbid disorders that may have shared neurobiological underpinnings[2,3]. Stress-related alterations in synaptic connections are thought to underlie network dysfunction, with functional magnetic resonance imaging (fMRI). Preclinical studies provide further evidence of lower synaptic density in models of chronic stress and depression, in PFC and hippocampal regions[16,17,18]

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