Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats.

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.

• Authors: Ellis Chika Onwordi, Els F Halff, Thomas Whitehurst, Ayla Mansur, Marie-Caroline Cotel, Lisa Wells, Hannah Creeney, David Bonsall, Maria Rogdaki, Ekaterina Shatalina, Tiago Reis Marques, Eugenii A Rabiner, Roger N Gunn, Sridhar Natesan, Anthony C Vernon, Oliver D Howes
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 246 (01 14 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 31937764 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-((3-(methylpyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one
• Antipsychotic Agents
• Membrane Glycoproteins
• Nerve Tissue Proteins
• Pyridines
• Pyrrolidinones
• SV2A protein, human

Topics

• Animals
• Antipsychotic Agents (therapeutic use)
• Brain (anatomy & histology, diagnostic imaging, metabolism)
• Female
• Frontal Lobe (diagnostic imaging, metabolism)
• Gyrus Cinguli (diagnostic imaging, metabolism)
• Humans
• Male
• Membrane Glycoproteins (metabolism)
• Nerve Tissue Proteins (metabolism)
• Organ Specificity
• Positron-Emission Tomography
• Pyridines (metabolism)
• Pyrrolidinones (metabolism)
• Rats
• Rats, Sprague-Dawley
• Schizophrenia (diagnostic imaging, drug therapy, metabolism)