The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging study
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. H...
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Nature Publishing Group
2025-03-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03269-8 |
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| author | Ellis Chika Onwordi Thomas Whitehurst Ekaterina Shatalina Richard Carr Ayla Mansur Atheeshaan Arumuham Martin Osugo Tiago Reis Marques Sameer Jauhar Susham Gupta Sofia Pappa Ravi Mehrotra Maja Ranger Nikola Rahaman Eugenii A. Rabiner Roger N. Gunn Sridhar Natesan Oliver D. Howes |
| author_facet | Ellis Chika Onwordi Thomas Whitehurst Ekaterina Shatalina Richard Carr Ayla Mansur Atheeshaan Arumuham Martin Osugo Tiago Reis Marques Sameer Jauhar Susham Gupta Sofia Pappa Ravi Mehrotra Maja Ranger Nikola Rahaman Eugenii A. Rabiner Roger N. Gunn Sridhar Natesan Oliver D. Howes |
| author_sort | Ellis Chika Onwordi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4a80c374df9d4dbfb0bdb73c58e0e76d |
| institution | DOAJ |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
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| series | Translational Psychiatry |
| spelling | doaj-art-4a80c374df9d4dbfb0bdb73c58e0e76d2025-08-20T03:03:40ZengNature Publishing GroupTranslational Psychiatry2158-31882025-03-011511810.1038/s41398-025-03269-8The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging studyEllis Chika Onwordi0Thomas Whitehurst1Ekaterina Shatalina2Richard Carr3Ayla Mansur4Atheeshaan Arumuham5Martin Osugo6Tiago Reis Marques7Sameer Jauhar8Susham Gupta9Sofia Pappa10Ravi Mehrotra11Maja Ranger12Nikola Rahaman13Eugenii A. Rabiner14Roger N. Gunn15Sridhar Natesan16Oliver D. Howes17Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College LondonInstitute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College LondonInstitute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College LondonPsychiatric Imaging Group, Medical Research Council, London Institute of Medical Sciences, Hammersmith HospitalIQVIAInstitute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College LondonInstitute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College LondonInstitute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College LondonDepartment of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King’s CollegeTower Hamlets Early Intervention Service, 51 Three Colts Lane, Bethnal Green, East London NHS Foundation TrustDepartment of Brain Sciences, Imperial College London, The Commonwealth Building, Hammersmith HospitalLakeside Unit, West Middlesex University Hospital, West London NHS TrustWestminster Community Rehabilitation Team & Bluebell Lodge, Central and North West London NHS Foundation TrustWestminster and Kensington and Chelsea Early Intervention Service, Central and North West London NHS Foundation Trust, Hathaway HouseInvicro, Burlington Danes BuildingDepartment of Brain Sciences, Imperial College London, The Commonwealth Building, Hammersmith HospitalInstitute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College LondonInstitute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College LondonAbstract 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.https://doi.org/10.1038/s41398-025-03269-8 |
| spellingShingle | Ellis Chika Onwordi Thomas Whitehurst Ekaterina Shatalina Richard Carr Ayla Mansur Atheeshaan Arumuham Martin Osugo Tiago Reis Marques Sameer Jauhar Susham Gupta Sofia Pappa Ravi Mehrotra Maja Ranger Nikola Rahaman Eugenii A. Rabiner Roger N. Gunn Sridhar Natesan Oliver D. Howes The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging study Translational Psychiatry |
| title | The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging study |
| title_full | The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging study |
| title_fullStr | The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging study |
| title_full_unstemmed | The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging study |
| title_short | The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging study |
| title_sort | relationship between cortical synaptic terminal density marker sv2a and glutamate early in the course of schizophrenia a multimodal pet and mrs imaging study |
| url | https://doi.org/10.1038/s41398-025-03269-8 |
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