Abstract
Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.
Highlights
Converging lines of evidence suggest glutamatergic dysfunction is involved in schizophrenia pathophysiology [1,2,3,4]
The groups were well matched in terms of age, gender, ethnicity and recent cannabis use, and there were no significant group differences in mean radioactivity of the positron emission tomography (PET) tracer administered, [11C]UCB-J plasma free fraction or centrum semiovale (CS) [11C] UCB-J volumes of distribution (VT) (Table 1)
The lower synaptic density marker levels, taken with the loss of the normal relationship between this and glutamate levels in the anterior cingulate cortex (ACC), could be explained by a loss of glutamatergic terminals in schizophrenia, such that a greater proportion of the remaining synaptic vesicle glycoprotein 2 A (SV2A) protein signal is from correlations in the ACC, we found no such differences between groups in the hippocampus, nor between groups in the strength of the [11C]UCB-J distribution volume ratio (DVR)-Glu/Cr correlations in either region of interest, nor between groups in the strength of the [11C]UCB-J VTGlu/Cr correlation in the hippocampus, using Fisher’s r-to-z
Summary
Converging lines of evidence suggest glutamatergic dysfunction is involved in schizophrenia pathophysiology [1,2,3,4]. Supporting this view, pharmacological modulation of glutamatergic function via Nmethyl-D-aspartate receptor (NMDAR) antagonism can induce positive and negative symptoms and cognitive deficits in healthy subjects and exacerbate them in schizophrenia patients [5, 6], with large effect sizes [7]. Genomic studies have identified associations between schizophrenia and variants in genes encoding and/or regulating glutamatergic proteins, including NMDAR and activityregulated cytoskeleton-associated protein complexes [8,9,10,11], which in turn regulate synaptic plasticity and cognition [12,13,14]. Postmortem studies in schizophrenia have found that cortical glutamatergic neurons display reductions in synaptophysin (a marker of synaptic density), dendritic spine density and Received: February 2021 Accepted: June 2021
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