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

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.