Abstract
Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis, but this has not been tested directly in vivo. Here, we investigated synaptic vesicle glycoprotein 2A (SV2A) levels and their relationship to symptoms and structural brain measures using [11C]UCB-J positron emission tomography in 18 patients with schizophrenia and 18 controls. We found significant group and group-by-region interaction effects on volume of distribution (VT). [11C]UCB-J VT was significantly lower in the frontal and anterior cingulate cortices in schizophrenia with large effect sizes (Cohen’s d = 0.8-0.9), but there was no significant difference in the hippocampus. We also investigated the effects of antipsychotic drug administration on SV2A levels in Sprague-Dawley rats using western blotting, [3H]UCB-J autoradiography and immunostaining with confocal microscopy, finding no significant effects on any measure. These findings indicate that there are lower synaptic terminal protein levels in schizophrenia in vivo and that antipsychotic drug exposure is unlikely to account for them.
Highlights
Background correction gFluorescence intensity/μm[2 ] anterior cingulate cortex (ACC) WM ACC Haloperidol STRHaloperidol staining was high in grey matter, but negligible in white matter (Fig. 4e)
There was a significant effect of group and region of interest (ROI) (F2,68 = 426.0, p < 0.0001) on [11C]UCB-J volume of distribution (VT)
There was a significant effect of group and of ROI (F2,68 = 510.9, p < 0.0001) on [11C]UCB-J distribution volume ratio (DVR)
Summary
Background correction gFluorescence intensity/μm[2 ] ACC WM ACC Haloperidol STRHaloperidol staining was high in grey matter, but negligible in white matter (Fig. 4e). Total SV2A intensity after background correction varied significantly by region (two-way ANOVA: F1,20 = 5.112 p = 0.035), but did so comparably between groups with no significant effect of treatment (F1,20 = 0.1412, p = 0.71) or treatment-byregion interaction (F1,20 = 0.2513, p = 0.62); Fig. 4g. To test whether the findings with HAL can be generalised to other antipsychotic drugs, we explored the effects of chronic OLZ administration on SV2A immunostaining intensity in the rat PFC and ACC (Supplementary Fig. 5). In agreement with the results from HAL treatment, chronic administration of OLZ did not induce any significant differences in SV2A immunostaining intensity (two-way ANOVA; effect of treatment: F1,14 = 0.0018, p = 0.97; region: F1,14 = 2.01, p = 0.18; treatment-by-region interaction: F1,14 = 1.87, p = 0.19)
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