Increased Expression of Synaptic Vesicle Glycoprotein 2A (SV2A) in the Brain of Chronic Diabetic Rats

Abstract

Aim/hypothesis: Diabetes mellitus has been reported to be a risk factor for cognitive dysfunction, depression, stroke, and seizures. Diabetic pathology is believed to interfere with synaptic plasticity. Synaptic vesicle glycoprotein 2A (SV2A) is a presynaptic vesicular protein and a popular synaptic density imaging marker. We investigated the effect of chronic hyperglycemia on the expression of SV2A in the cerebral cortex and hippocampus of rats and compared it to other presynaptic markers, such as GAP43, Synaptotagmin-1, and SNAP25.

Methods: A single dose of streptozotocin (STZ, 45 mg/kg, i.p.) was administered to adult male rats, resulting in sustained hyperglycemia and reduced plasma insulin levels. Controls were injected with saline, and another STZ group was treated with insulin. Fasting blood glucose (FBG) and fasting plasma insulin (FPI) levels were monitored throughout the observation period, and the level of SV2A was determined by radioligand, [³H]UCB-J, binding capacity using in-vitro autoradiography and by ELISA. Similarly, the tissue concentration of other synaptic proteins GAP43, SNAP25, and SYN1 was measured using ELISA. Quantitative RT-qPCR was performed to measure Sv2a, Sv2b, and Sv2c transcripts. Finally, hippocampal and cortical glutamate levels were measured in all tissues.

Results: [³H]UCB-J binding, SV2A (pg/mg protein) and Sv2a mRNA levels were significantly higher in hyperglycemic rats. The SV2A concentration detected by ELISA and [³H]UCB-J binding showed, as expected, a positive correlation with each other. The same positive and significant correlation was seen between SV2A, FBG, and glutamate l levels across animals (p ≤ 0.001). Notably, there was no difference and no linearity between FBG and other presynaptic markers such as GAP43, Synaptotagmin-1, and SNAP25.

Conclusions: Unlike other synaptic markers (e.g., SNAP25, SYN-1), SV2A levels rise independently of synaptic density, correlating with elevated glutamate and metabolic activity. These findings raise doubt about SV2A's role as a pure synaptic density marker.

Keywords: SV2A; diabetes; glutamate; hyperglycemia; rat; synapse.