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. 2025 Mar 1;15(1):70.
doi: 10.1038/s41398-025-03269-8.

The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging study

Ellis Chika Onwordi  1   2   3   4   5 , Thomas Whitehurst  6   7   8   9 , Ekaterina Shatalina  6   7   8 , Richard Carr  7   8   10 , Ayla Mansur  11 , Atheeshaan Arumuham  6   7   8 , Martin Osugo  6   7   8 , Tiago Reis Marques  6   7   8 , Sameer Jauhar  12 , Susham Gupta  13 , Sofia Pappa  14   15 , Ravi Mehrotra  16 , Maja Ranger  17 , Nikola Rahaman  18 , Eugenii A Rabiner  19   20 , Roger N Gunn  14   19 , Sridhar Natesan  6   7   8 , Oliver D Howes  21   22   23
Affiliations

The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging study

Ellis Chika Onwordi et al. Transl Psychiatry. .

Abstract

Loss of glutamatergic terminals is hypothesised to contribute to excitation-inhibition imbalance in schizophrenia, supported by evidence that the normal positive association between glutamate concentrations and synaptic terminal density is not found in patients with chronic schizophrenia. However, it is unknown whether the relationship between synaptic terminal density and glutamate levels is altered early in the course of illness. To address this, we investigated [11C]UCB-J distribution volume ratio (DVR) and glutamatergic markers in healthy volunteers (HV) and in antipsychotic-naïve/free patients with schizophrenia (SCZ) recruited from first-episode psychosis services. Forty volunteers (HV n = 19, SCZ n = 21) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the anterior cingulate cortex (ACC) and left hippocampus to index [11C]UCB-J DVR and creatine-scaled glutamate (Glu/Cr) and glutamate in combination with glutamine (Glx/Cr). In the HV but not SCZ group, [11C]UCB-J DVR was significantly positively associated with Glu/Cr (Spearman's rho = 0.55, p = 0.02) and Glx/Cr (Spearman's rho = 0.73, p = 0.0004) in the ACC, and with Glu/Cr in the left hippocampus (Spearman's rho = 0.77, p = 0.0001). DVR was significantly lower in the ACC in the SCZ group compared to the HV group (Kolmogorov-Smirnov Z = 1.44, p = 0.03). Together, these findings indicate that the normal relationship between levels of a synaptic terminal density marker and levels of glutamate is disrupted early in the course of schizophrenia. This is consistent with the hypothesis that there is loss of glutamatergic terminals at illness onset.

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Conflict of interest statement

Competing interests: SP has received honoraria as a consultant or speaker from Janssen, Recordati, Sunovion, Lundbeck, Rovi and Otsuka and a research grant from Recordati, all outside the submitted work. EAR and RNG are employees of Invicro LLC. AM was an employee of Invicro LLC during the completion of much of this work. TRM has received honoraria for speaking and chairing from Lundbeck, Janssen, and Astellas and received honoraria to participate in advisory boards organized by Angelini Pharmaceuticals. In the last 3 years, SJ has given nonpromotional educational talks for Lundbeck, Janssen, and Sunovion. ODH has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche, and Viatris/Mylan. ODH has a patent for the use of dopaminergic imaging. The other authors report no biomedical financial interests or potential conflicts of interest.

Figures

Fig. 1
Fig. 1
1H-MRS voxel position in the anterior cingulate cortex (top panel) and left hippocampus (bottom panel).
Fig. 2
Fig. 2. [11C]UCB-J distribution volume ratio (DVR) and levels of glutamate (Glu/Cr) in the anterior cingulate cortex (ACC).
Significant positive relationship between [11C]UCB-J DVR and Glu/Cr levels in the ACC in the healthy volunteer group (HV, rho = 0.55, p = 0.02), and no significant relationship in the schizophrenia group (SCZ, rho = 0.30, p = 0.18). Linear regression line shown.
Fig. 3
Fig. 3. [11C]UCB-J distribution volume ratio (DVR) and levels of glutamate (Glu/Cr) in the left hippocampus.
Significant positive relationship between [11C]UCB-J DVR and Glu/Cr levels in the left hippocampus in the healthy volunteer group (HV, Spearman’s rho = 0.77, p = 0.0001) and no significant relationship in the schizophrenia group (SCZ, rho = −0.03, p = 0.89). Linear regression line shown.
See this image and copyright information in PMC

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